RU2297418C9 - Novel condensed derivatives of imidazole, inhibitors of dipeptidyl peptidase iv, pharmaceutical composition, method of treatment and using based on thereof - Google Patents

Abstract

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel condensed derivatives of imidazole that are inhibitors of dipeptidyl peptidase IV. Invention describes compound represented by the following formula (I):

or its salt or hydrate wherein T¹ represents monocyclic 5-6-membered heterocyclic group comprising one or two nitrogen atoms in ring that can comprise one or more amino-groups as substitutes; X represents (C₂-C₆)-alkenyl group that can comprise one or more substitutes, (C₂-C₆)-alkynyl group, phenyl group that can comprise one or some substitutes chosen from alkyl group or halogen atom or phenyl-(C₁-C₆)-alkyl group; each Z¹ and Z² represents independently nitrogen atom or group of the formula -CR²=; each R¹ and R² represents independently group of the formula -A⁰-A¹-A² wherein A⁰ represents a single bond or (C₁-C₆)-alkylene group that can comprise 1-3 substitutes chosen from group B consisting of given below substitutes; A¹ represents a single bond, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, carbonyl group, group represented by formula -O-CO-, group represented by formula -CO-O-, group represented by formula -NR^A-, group represented by formula -CO-NR^A-, group represented by formula -NR^A-CO-, group represented by formula -SO₂-NR^A-, or group represented by formula -NR^A-SO₂-; each A² and R^A represents independently hydrogen atom, halogen atom, cyano-group, (C₁-C₆)-alkyl group, (C₃-C₈)-cycloalkyl group, (C₂-C₆)-alkenyl group, (C₂-C₆)-alkynyl group, (C₆-C₁₀)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, 5-10-membered heteroaryl-(C₁-C₆)-alkyl group, (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl group or (C₂-C₇)-alkylcarbonyl group wherein each A² and R^A can comprise independently 1-3 substitutes chosen from the given below group of substitutes D: when Z² represents group of the formula -CR²= then R¹ and R² can form in common 5-7-membered ring with exception cases when: [1] R¹ represents hydrogen atom; Z¹ represents nitrogen atom, and Z² represents group -CH=; and [2] Z¹ represents nitrogen atom and Z² represents group -C(OH)=; <group of substitutes B>. Group of substitutes B represents group comprising: hydroxyl group, mercapto-group, cyano-group, nitro-group, halogen atom, trifluoromethyl group, (C₁-C₆)-alkyl group that can comprise one or some substitutes, (C₃-C₈)-cycloalkyl group, (C₂-C₆)-alkenyl group, (C₂-C₆)-alkynyl group, (C₆-C₁₀)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, (C₁-C)-alkoxy-group, (C₁-C₆)-alkylthio-group, group represented by formula -SO₂-NR^B1-R^B2, group represented by formula -NR^B1-CO-R^B2, group represented by formula -NR^B1-R^B2 (wherein each R^B1 and R^B2 represents independently hydrogen atom or (C₁-C₆)-alkyl group), group represented by formula -CO-R^B3 (wherein R^B3 represents 4-8-membered heterocyclic group), group represented by formula -CO-R^B4-R^B5, and group represented by formula -CH₂-CO-R^B4-R^B5 wherein R^B4 represents a single bond, oxygen atom or group represented by formula -NR^B6- wherein each R^B5 and R^B6 represents independently hydrogen atom, (C₁-C₆)-alkyl group, (C₃-C₈)-cycloalkyl group, (C₂-C₆)-alkenyl group, (C₂-C₆)-alkynyl group, (C₆-C₁₀)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocycle-(C₁-C₆)-alkyl group, (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl group or 5-10-membered heteroaryl-(C₁-C₆)-alkyl group. Also, invention describes inhibitor, pharmaceutical composition, method of treatment and using based on thereof. Invention describes novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

33 cl, 3 tbl, 352 ex

Description

The present invention relates to new condensed imidazole derivatives, which are valuable inhibitors of dipeptidyl peptidysis-IV (DPPIV), and their use.

Description of the prior art

Dipeptidyl peptidysis IV (DPPIV) is a serine protease that specifically hydrolyzes the dipeptide X-Pro (X = arbitrary amino acid) at the free N-terminus of the polypeptide chain.

Hormones that stimulate glucose-dependent insulin secretion, known as incretins (GLP-1: glucagon-like peptide-1 and GIP: glucose-dependent insulinotropic polypeptide), released in the digestive tract after a meal, are rapidly hydrolyzed and inactivated by DPPIV. When hydrolysis is suppressed by DPPIV, incretin (GLP-1 or GIP) is enhanced, which in turn increases glucose-stimulated insulin secretion from pancreatic β-cells. This has been shown to improve hyperglycemia in the oral glucose tolerance test (see Diabetologia 1999 Nov, 42 (11), 1324-31). In addition, GLP-1 is known to be involved in processes that reduce appetite and suppress the desire for food. It is also reported that GLP-1 affects the protective functions of pancreatic β-cells, enhancing their differentiation and proliferation. Thus, a DPPVI inhibitor can serve as a useful therapeutic and prophylactic agent in the treatment of diseases associated with the action of GLP-1 and / or GIP, such as obesity and diabetes.

In addition, there are many reports confirming the relationship between dipeptidyl peptidase IV and the various diseases described below. Thus, a DPPIV inhibitor can serve as a therapeutic agent in diseases such as

(1) prophylactic and therapeutic agents for treating AIDS (see Science 1993, 262, 2045-2050),

(2) prophylactic and therapeutic agents for the treatment of osteoporosis (see Clinical Chemistry 1988, 34, 2499-2501),

(3) prophylactic and therapeutic agents for the treatment of gastrointestinal disorders (see Endocrinology 2000, 141, 4013-4020),

(4) prophylactic and therapeutic agents for the treatment of diabetes mellitus, obesity and hyperlipidemia (see Diabetes 1998, 47, 1663-1670, and Life Sci 2000, 66 (2), 91-103),

(5) prophylactic and therapeutic agents for the treatment of angiogenesis (see Agents and Action 1991, 32, 125-127),

(6) prophylactic and therapeutic agents for the treatment of infertility (see International Publication WO 00/56296),

(7) prophylactic and therapeutic agents for treating inflammatory conditions, autoimmune diseases, and chronic rheumatoid arthritis (see The Journal of Immunology 2001, 166, 2041-2048) and

(8) prophylactic and therapeutic agents for the treatment of cancer (see Br. J. Cancer 1999, March, 79 (7-8), 1042-8, and J. Androl 2000 March-April, 21 (2), 220-6 )

Some DPPIV inhibitors are described in US Pat. 2002/0161001; International Publication WO 03/004496 and US Patent Publication No. 2002/0198205. However, there is no evidence of a DPPIV inhibitor with a hypoxanthine or imidazopyridazinone structure.

As follows from the foregoing, numerous attempts have been made to search for compounds with DPPIV-inhibitory activity, which could be used as therapeutic agents. However, to date, no compound has been found that combines high DPPIV-inhibitory activity with high clinical efficacy. An object of the present invention is to provide compounds with DPPIV-inhibitory activity, which could be used as prophylactic, therapeutic and sedative agents in the treatment of diabetes mellitus and related diseases.

SUMMARY OF THE INVENTION

The authors of the present invention have conducted extensive research in the above field. The result of these studies was the synthesis of new condensed imidazole derivatives, including hypoxanthine and imidazopyridazinone derivatives. In the implementation of the present invention, the authors also found that the obtained compounds have excellent DPPIV-inhibitory activity. The present invention covers

[1] a compound represented by the following formula, a salt or hydrate thereof

where T ¹ represents a monocyclic or bicyclic 4-12-membered heterocyclic group containing one or two nitrogen atoms in the ring, and which may have one or more substituents;

X represents a C _1-6 alkyl group which may contain one or more substituents, a C _2-6 alkenyl group which may contain one or more substituents, a C _2-6 alkynyl group which may contain one or more substituents, C _{6 A -10} aryl group which may contain one or more substituents, a 5-10 membered heteroaryl group which may contain one or more substituents, a C _6-10 aryl C _1-6 alkyl group which may contain one or more substituents, or 5-10 membered getter aryl C _1-6 alkyl group which may contain one or more substituents;

Z ¹ and Z ² each independently represent a nitrogen atom or a group represented by the formula —CR ² =;

R ¹ and R ² each independently represent a group represented by the formula —A ⁰ —A ¹ —A ² (wherein A ⁰ is a single bond or a C _1-6 alkylene group which may contain 1-3 substituents selected from group B, including the substituents indicated below;

And ¹ represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O — CO—, a group represented by the formula —CO — O—, a group represented by the formula —NR ^A - a group represented by the formula —CO — NR ^A— , a group represented by the formula —NR ^A —CO—, a group represented by the formula —SO ₂ —NR ^A -, or a group represented by the formula —NR ^A —SO ₂ -;

A ² and R ^A each independently represent a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{6- 10} aryl group, 5-10 membered heteroaryl group, 4-8 membered heterocyclic group, 5-10 membered heteroaryl C _1-6 alkyl group C _6-10 aryl C _1-6 alkyl group or C _2-7 alkylcarbonyl group ;

wherein A ² and R ^A each, independently, may contain 1-3 substituents selected from the group of substituents B indicated below:

when Z ² represents a group represented by the formula —CR ² =, R ¹ and R ² may together be a 5-7 membered ring,

unless [1] R ¹ represents a hydrogen atom; Z ¹ represents a nitrogen atom and Z ² represents —CH =; [2] Z ¹ represents a nitrogen atom and Z ² represents —C (OH) =.

<Deputy group B>

Substituent group B is a group comprising a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C _1-6 alkyl group which may contain one or more substituents, a C _3-8 cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _6-10 aryl group, 5-10 membered heteroaryl group, 4-8 membered heterocyclic group, C _1-6 alkoxy group, C _1-6 alkylthio group, the group represented by the formula -SO ₂ -NR ^B1 -R ^B2 , a group represented by the formula -NR ^B1 -CO-R ^B2 , groups y represented by the formula —NR ^B1 —R ^B2 (where R ^B1 and R ^B2 each independently represents a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^B3 (where R ^B3 represents 4 -8 membered heterocyclic group), a group represented by the formula —CO — R ^B4 —R ^B5 , and a group represented by the formula —CH ₂ —CO — R ^B4 —R ^B5 (where R ^B4 represents a single bond, an oxygen atom, or a group represented by the formula —NR ^B6 -; R ^B5 and R ^B6 each independently represent a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, 5 A 10-membered heteroaryl group, a 4-8-membered heterocyclyl C _1-6 alkyl group, a C _6-10 aryl C _1-6 alkyl group or a 5-10-membered heteroaryl C _1-6 alkyl group)), and

[2] the compound according to [1], or a salt or hydrate thereof, wherein T ¹ represents a group represented by the following formula:

(where n and m, each independently, is 0 or 1), which may have one or more substituents;

azetidin-1-ilen group, which may have one or more substituents;

a pyrrolidin-1-yl group which may have one or more substituents;

piperidin-1-ilen group, which may have one or more substituents, or

an azepan-1-yl group which may have one or more substituents;

[3] the compound according to [1], or a salt or hydrate thereof, wherein T ¹ represents a group represented by the following formula:

(where n and m, each independently, is 0 or 1);

azetidin-1-ilen group, which may contain an amino group;

pyrrolidin-1-ilen group, which may contain an amino group;

piperidin-1-ilen group, which may contain an amino group, or

an azepan-1-yl group which may contain an amino group;

[4] the compound according to [1], or a salt or hydrate thereof, wherein T ¹ is a piperazin-1-yl group or a 3-aminopiperidin-1-yl group;

[5] the compound according to [1], or a salt or hydrate thereof, wherein T ¹ is a piperazin-1-yl group;

[6] the compound according to any one of [1] to [5], or a salt or hydrate thereof, wherein X is a group represented by the formula —X ¹ —X ² (where X ¹ is a single bond or a methylene group which may have one or more substituents; X ² represents a C _2-6 alkenyl group which may have one or more substituents, a C _2-6 alkynyl group which may have one or more substituents, or a phenyl group which may have one or more substitutes);

[7] the compound according to any one of [1] to [5], or a salt or hydrate thereof, wherein X is a group represented by the formula —X ¹¹ —X ¹² (where X ¹¹ is a single bond or a methylene group; X ¹² represents a C _2-6 alkenyl group, a C _2-6 alkynyl group or a phenyl group which may have one or more substituents);

[8] the compound according to [6] or [7], or a salt or hydrate thereof, wherein the phenyl group, which may have one or more substituents, is a phenyl group, which may have in position 2 a substituent selected from the group consisting of from a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a vinyl group, a methoxy group, an ethoxy group, an acetyl group, a cyano group, a formyl group, and a C _2-7 alkoxycarbonyl group;

[9] the compound according to any one of [1] to [5], or a salt or hydrate thereof, wherein X represents a 3-methyl-2-buten-1-yl group, a 2-butyn-1-yl group, a benzyl group or a 2-chlorophenyl group;

[10] the compound according to any one of [1] to [5], or a salt or hydrate thereof, wherein X is a 2-butyn-1-yl group;

[11] the compound according to any one of [1] to [10], or a salt or hydrate thereof, wherein any of the groups Z ¹ or Z ² represents a nitrogen atom;

[12] the compound according to any one of [1] to [10], or a salt or hydrate thereof, wherein

Z ¹ represents a nitrogen atom and

Z ² represents a group represented by the formula —CR ² =

(where R ² has the meanings specified in paragraph [1]);

[13] the compound according to any one of [1] to [10], or a salt or hydrate thereof, wherein

Z ² represents a nitrogen atom and

Z ¹ represents a group represented by the formula —CR ² =

(where R ² has the meanings indicated in [1]);

[14] the compound according to any one of [1] to [13], or a salt or hydrate thereof, wherein R ¹ represents a hydrogen atom or a group represented by the formula -A ¹⁰ -A ¹¹ -A ¹²

(where A ¹⁰ represents a C _1-6 alkenyl group, which may have 1-3 substituents selected from the following substituent group C;

A ¹¹ represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group;

A ¹² represents a hydrogen atom, a C _6-10 aryl group which may have 1-3 substituents selected from the following substituent group C, a 5-10 membered heteroaryl group which may have 1-3 substituents selected from the following substituent groups C, a 5-10 membered heteroaryl C _1-6 alkyl group which may have 1-3 substituents selected from the following substituent group C, or a C _6-10 aryl C _1-6 alkyl group which may have 1 -3 substituents selected from the following substituent group C:

<Deputy group C>

The substituent group C represents a group comprising a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR ^C1- R ^C2 (where each of R ^C1 and R ^C2 independently represents a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^C3 —R ^C4 and a group represented by the formula —CH ₂ —CO — R ^C3 -R ^C4 (where R ^C3 represents a single bond, an oxygen atom or a group represented by the formula -NR ^C5 -; R ^C4 and R ^C5 each independently represent a hydrogen atom or a C _1-6 alkyl group);

[15] the compound according to any one of [1] to [13], or a salt or hydrate thereof,

where R ¹ represents a hydrogen atom, a C _1-6 alkyl group which may have 1-3 substituents selected from the group of substituents C described below, a 5-10 membered heteroaryl C _1-6 alkyl group which may have a 1- 3 substituents selected from substituent group C described below, or a C _6-10 aryl C _1-6 alkyl group which may have 1-3 substituents selected from substituent group C described below:

<Deputy group C>

The substituent group C represents a group comprising a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a trifluoromethyl group represented by the formula —NR ^C1 -R ^C2 (where each of R ^C1 and R ^C2 independently represents a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^C3 —R ^C4 , and a group represented by the formula —CH ₂ —CO — R ^C3 - R ^C4 (where R ^C3 represents a single bond, an oxygen atom or a group represented by the formula —NR ^C5 -; R ^C4 and R ^C5 each independently represent a hydrogen atom or a C _1-6 alkyl group));

[16] the compound according to [14] or [15], or a salt or hydrate thereof, wherein the substituent group C is a group comprising a cyano group, a C _1-6 alkoxy group, a C _2-7 alkoxycarbonyl group and a halogen atom;

[17] the compound according to any one of [1] to [13], or a salt or hydrate thereof, wherein R ¹ is a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a 2-methoxyethyl group, or 4-methoxycarbonylpyridin-2 an alkyl group;

[18] the compound according to any one of [1] to [13], or a salt or hydrate thereof, wherein R ¹ is a methyl group or a 2-cyanobenzyl group;

[19] the compound according to any one of [1] to [18], or a salt or hydrate thereof,

where R ² represents a hydrogen atom, a cyano group or a group represented by the formula -A ²¹ -A ²²

(where A ²¹ represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O — CO—, a group represented by the formula —CO — O—, a group represented by the formula —NR ^A2 -, a group represented by the formula —CO — NR ^A2 -, or a group represented by the formula NR ^A2 —CO—;

A ²² and R ^A2 each independently represent a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group A 5-10 membered heteroaryl group, a 4-8 membered heterocyclic group, a 5-10 membered heteroaryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkyl group,

wherein A ²² and R ^A2 , each independently, may have 1-3 substituents selected from the group of substituents D described below.

<Deputy group D>

The substituent group D is a group comprising a hydroxyl group, a cyano group, a nitro group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR ^D1 —R ^D2 (where R ^D1 and R ^D2 each independently represent a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^D3 (where R ^D3 represents a 4-8 membered heterocyclic group), and a group represented by the formula -CO-R ^D4 -R ^D5 (where R ^D4 represents a single bond, oxygen atom, or a group represented by formula -NR ^D6 -; R ^D5 and R ^D6, each independently represent a hydrogen atom, a C _3-8 cycloalkyl group or a C _1-6 alkyl group));

[20] the compound according to any one of [1] to [18], or a salt or hydrate thereof,

where R ² represents a hydrogen atom, a cyano group, a carboxy group, a C _2-7 alkoxycarbonyl group, a C _1-6 alkyl group, a group represented by the formula —CONR ^D7 R ^D8 (where R ^D7 and R ^D8 each independently represent a hydrogen atom or a C _1-6 alkyl group), or a group represented by the formula -A ²³ -A ²⁴

(where A ²³ represents an oxygen atom, a sulfur atom or a group represented by the formula —NR ^A3 -;

A ²⁴ and R ^A3 each independently represent a hydrogen atom, a C _1-6 alkyl group which may contain a substituent selected from the following substituent group D1, a C _3-8 cycloalkyl group which may have a substituent selected from the following substituent groups D1; a C _2-6 alkenyl group which may have a substituent selected from the following substituent group D1; a C _2-6 alkynyl group which may have a substituent selected from the following substituent group D1; a phenyl group which may have s an substituent selected from the following D1 substituent group, or a 5-10 membered heteroaryl group which may have a substituent selected from the following D1 substituent group.

<Deputy group D1>

The substituent group D1 is a group comprising a carboxy group, a C _2-7 alkoxycarbonyl group, a C _1-6 alkyl group, a group represented by the formula —CONR ^D7 R ^D8 (where R ^D7 and R ^D8 each independently represent a hydrogen atom or C _1-6 alkyl group), a pyrrolidin-1-ylcarbonyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group);

[21] the compound according to any one of [1] to [18], or a salt or hydrate thereof,

where R ² represents a hydrogen atom, a cyano group, a C _1-6 alkoxy group or a group represented by the formula -A ²⁵ -A ²⁶

(where A ²⁵ represents an oxygen atom, a sulfur atom or a group represented by the formula —NR ^A4 -;

A ²⁶ and R ^A4 each independently represent a hydrogen atom, a C _1-6 alkyl group having a substituent selected from the group of substituents D1 described below, a C _3-8 cycloalkyl group having a substituent selected from the specified group of substituents D1, described below, or a phenyl group having a substituent selected from the group of substituents D1 described below:

<Deputy group D1>

The substituent group D1 is a group comprising a carboxy group, a C _2-7 alkoxycarbonyl group, a C _1-6 alkyl group, a group represented by the formula —CONR ^D7 R ^D8 (where R ^D7 and R ^D8 each independently represent a hydrogen atom or C _1-6 alkyl group), a pyrrolidin-1-ylcarbonyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group);

[22] the compound according to any one of [1] to [18], or a salt or hydrate thereof,

where R ² represents a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group, or a group represented by the formula

(where A ²⁷ represents an oxygen atom, a sulfur atom or —NH—; A ²⁸ and A ²⁹ each independently represent a hydrogen atom or a C _1-6 alkyl group);

[23] the compound according to any one of [1] to [18], or a salt or hydrate thereof, wherein R ² represents a hydrogen atom, a cyano group or a 2-carbamoylphenyloxy group;

[24] the compound according to [1], or a salt or hydrate thereof, wherein the compound of formula (I) above is any compound selected from the group consisting of

7- (2-butynyl) -2-cyano-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one,

3- (2-butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one,

2- (3-aminopiperidin-1-yl) -3- (2-butynyl) -5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one,

2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide,

7- (2-butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile and

2- [3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzonitrile;

[25] a pharmaceutical agent comprising a compound according to any one of [1] to [24];

[26] a dipeptidyl peptidase IV inhibitor comprising a compound according to any one of [1] to [24];

[27] a pharmaceutical composition comprising a compound according to any one of [1] to [24] and an excipient used in the preparation of a preparation;

[28] a prophylactic or therapeutic agent for the treatment of diabetes mellitus, containing the compound according to any one of [1] to [24];

[29] a prophylactic or therapeutic agent containing a compound according to any one of [1] to [24] for the treatment of diabetes mellitus, obesity, hyperlipidemia, AIDS, osteoporosis, gastrointestinal disturbances, angiogenesis, infertility, inflammatory diseases, allergic diseases or cancer;

[30] an immunomodulator, a hormone modulator, or an anti-rheumatic drug, comprising a compound according to any one of [1] to [24];

[31] a method for the prevention or treatment of a disease in which the inhibition of dipeptidyl peptidase IV is effective, comprising administering to a patient a compound according to any one of [1] to [24], or a salt or hydrate thereof in a pharmaceutically effective amount;

[32] the use of a compound according to any one of [1] to [24], or a salt or hydrate thereof, in the manufacture of a pharmaceutical agent;

[33] the use of a compound according to any one of [1] to [24], or a salt or hydrate thereof, in the manufacture of a therapeutic or prophylactic agent for treating a disease in which the inhibition of dipeptidyl peptidase IV is effective;

[34] a compound represented by the following formula, or a salt thereof, or a hydrate thereof:

where T ⁰ represents a group T ¹ described above in [1], a pyridyl group which may have one or more substituents, a pyridinium group which may have one or more substituents, a group represented by the following formula:

a group which may contain one or more substituents represented by the following formula:

(where n and m, each independently, are 0 or 1), or a group which may have one or more substituents represented by the following formula:

(where n and m, each independently, are 0 or 1);

X ⁰ represents a C _3-8 cycloalkyl group which may have one or more substituents, a C _1-6 alkyl group which may have one or more substituents, a C _2-6 alkenyl group which may have one or more substituents, C _{A 2-6} alkynyl group which may have one or more substituents, a C _2-6 aryl group which may have one or more substituents, a 5-10 membered heteroaryl group which may contain one or more substituents, C _6-10 aryl C _1-6 alkyl group which may Met one or more substituents, or a 5-10 membered heteroaryl _C1-6 alkyl group which may have one or more substituents;

R ¹ , Z ¹ and Z ² have the meanings indicated above in [1];

[35] a compound represented by the following formula, or a salt thereof, or a hydrate thereof:

where R ¹ , R ² , T ¹ , Z ¹ and Z ² have the meanings indicated above in [1];

[36] a compound represented by the following formula, or a salt thereof, or a hydrate thereof:

where R ¹ , R ² , T ¹ have the meanings indicated above in [1];

[37] the compound represented by the following formula, or a salt or hydrate thereof:

where R ¹ has the meanings indicated above in [1];

R ^p5 represents a tert-butoxycarbonyloxy group, a trityl group or a group represented by the formula —SO ₂ NH ₂ , and

T ¹⁰ represents a halogen atom or a hydrogen atom;

[38] a compound represented by the following formula, or a salt thereof, or a hydrate thereof:

where R ¹ has the meanings indicated above in [1], and

T ¹¹ represents a halogen atom or a group represented by the following formula:

(where T ¹³ represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a formyl group);

[39] a compound represented by the following formula, or a salt thereof, or a hydrate thereof

where R ¹ and X have the meanings indicated above in [1], respectively, and

T ¹² represents a halogen atom;

[40] a compound represented by the following formula, or a salt thereof, or a hydrate thereof,

where X has the meanings indicated above in [1], excluding the meaning when X represents a benzyl group;

T ²¹ and T ²² each independently represent a halogen atom and

T ¹¹ represents a halogen atom or a group represented by the following formula:

(where T ¹³ represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a formyl group);

[41] a compound represented by the following formula, or a salt or hydrate thereof

where X and R ¹ have the meanings indicated above in [1], respectively;

T ²² represents a halogen atom and

T ¹³ represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a formyl group;

[42] a compound represented by the following formula, or a salt or hydrate thereof

where the ring T ¹ represents a monocyclic or bicyclic 6-12 membered heterocyclic group containing two nitrogen atoms in the ring, which may have one or more substituents;

X represents a C _1-6 alkyl group which may have one or more substituents, a C _2-6 alkenyl group which may have one or more substituents, a C _2-6 alkynyl group which may have one or more substituents, C _{6 A -10} aryl group which may have one or more substituents, a 5-10 membered heteroaryl group which may have one or more substituents, a C _6-10 aryl C _1-6 alkyl group which may have one or more substituents, or 5-10 membered heteroaryl C _1-6 alkyl group which may have one or more substituents;

X may form a bond with the atom that is part of the ring T ¹ ;

Z ¹ and Z ² each independently represent a nitrogen atom or a group represented by the formula —CR ² =;

R ¹ and R ² independently represent a hydrogen atom, a 4-8 membered heterocyclic group which may have one or more substituents, or a group represented by the formula —A ⁰ —A ¹ —A ²

(where A ⁰ represents a single bond or a C _1-6 alkylene group which may have 1-3 substituents selected from substituent group B described below; A ¹ represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group a group, a carbonyl group, a group represented by the formula —O — CO—, a group represented by the formula —CO — O—, a group represented by the formula —NR ^A -, a group represented by the formula —CO — NR ^A -, a group represented by the formula — NR ^A —CO, a group represented by the formula —SO ₂ —NR ^A - or a group ln formula -NR ^A -SO ₂ -;

A ² and R ^A each independently represent a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, 5 A 10-membered heteroaryl group or a 4-8 membered heterocyclic group, wherein A ² and R ^A each independently may have 1-3 substituents selected from substituent group B described below:

except where (i) both R ¹ and R ² are hydrogen atoms and (ii) R ² is a hydroxyl group.

<Deputy group B>

Substituent group B is a group comprising a hydroxyl group, a cyano group, a halogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group A 5-10 membered heteroaryl group, a 4-8 membered heterocyclic group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a group represented by the formula —CO — R ^B —R ^B2 (where R ^B is a single bond, an oxygen atom, a group represented by formula-NR ^B3 -; R ^B2 and R ^B3, each independently represent a hydrogen atom, a C _1-6 al yl group, a _C3-8 cycloalkyl group, _C2-6 alkenyl group, _C2-6 alkynyl group, a C _6-10 aryl group, 5-10-membered heteroaryl group, C _6-10 aryl C _1-6 alkyl group , 5-10 membered heteroaryl C _1-6 alkyl group, 1-pyrrolidinyl group, 1-morpholinyl group, 1-piperazinyl group or 1-piperidyl group)).

Preferred Embodiment

The present invention is illustrated in detail below.

For convenience of description, the structural formula of the compound here sometimes depicts a specific isomer. However, the compounds of the present invention can include all possible isomers, such as structurally possible geometric isomers, optical isomers formed due to the presence of asymmetric carbon atoms, stereoisomers, tautomers and mixtures of isomers, and they are not limited to the formulas used for convenience in the description, and can represent any of two isomers or a mixture of both isomers. Thus, the compounds of the present invention can be any optically active compounds whose molecules or racemates contain an asymmetric carbon atom, and they are not limited to any of these forms, but include both. In addition, the compounds of the present invention may exhibit crystalline polymorphism, but even then they are not limited to a particular polymorph, and may be any of such crystalline forms or exist as a mixture of two or more crystalline forms. The compounds of the present invention also include both anhydrous and hydrated forms. Substances resulting from the in vivo metabolism of the compounds of the present invention are also included in the scope of the claims.

The following describes in detail the terms and symbols used in the present invention.

As used here, the expression "C _1-6 alkyl group" refers to a linear or branched alkyl group containing 1-6 carbon atoms, which is a monovalent group obtained by removing any hydrogen atom from an aliphatic hydrocarbon molecule containing 1-6 carbon atoms and, in particular, includes, for example, a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-butyl group, 2 -butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-1-butyl group, 3-methyl-1-butyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 2,2-dimethyl-1 -propyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-1-pentyl group, 3-methyl-1-pentyl group, 4-methyl-1-pentyl group, 2-methyl- 2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 2-methyl-3-pentyl group, 3-methyl-3-pentyl group, 2,3-dimethyl-1-butyl group, 3,3-dimethyl-1-butyl group, 2,2-dimethyl-1-butyl group, 2-ethyl-1-butyl th group, 3,3-dimethyl-2-butyl group and 2,3-dimethyl-2-butyl group.

As used here, the expression "C _2-6 alkenyl group" refers to a linear or branched alkenyl group containing 2-6 carbon atoms, and, in particular, includes, for example, a vinyl group, allyl group, 1-propenyl group, 2- propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, pentenyl group and hexenyl group.

As used here, the expression "C _2-6 alkynyl group" refers to a linear or branched alkynyl group containing 2-6 carbon atoms, and, in particular, includes, for example, an ethynyl group, a 1-propynyl group, a 2-propynyl group, butynyl group, pentynyl group, hexynyl group.

As used here, the expression "C _3-6 cycloalkyl group" refers to a cyclic aliphatic hydrocarbon group containing 3-8 carbon atoms, and, in particular, includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctyl group.

As used here, the expression "C _1-6 alkylene group" refers to a divalent group obtained by the removal of another arbitrary hydrogen atom from a "C _1-6 alkyl group" having the above meanings, and, in particular, includes, for example, methylene group, 1,2-ethylene group, 1,1-ethylene group, 1,3-propylene group, tetramethylene group, pentamethylene group and hexamethylene group.

As used here, the expression "C _3-8 cycloalkylene group" refers to a divalent group obtained by removing another arbitrary hydrogen atom from the "C _3-8 cycloalkyl group" having the above meanings.

As used herein, the term “C _1-6 alkoxy group” refers to an oxy group bonded to a “C _1-6 alkyl group” as defined above, and particularly includes, for example, a methoxy group, an ethoxy group, a 1-propyloxy group, a 2-propyloxy group , 2-methyl-1-propyloxy group, 2-methyl-2-propyloxy group, 1-butyloxy group, 2-butyloxy group, 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methyl-1-butyloxy group, 3-methyl-1 -butyloxy group, 2-methyl-2-butyloxy group, 3-methyl-2-butyloxy group, 2,2-dimethyl-1-propyloxy group, 1-hexyloxy group, 2-hexyl xy group, 3-hexyloxy group, 2-methyl-1-pentyloxy group, 3-methyl-1-pentyloxy group, 4-methyl-1-pentyloxy group, 2-methyl-2-pentyloxy group, 3-methyl-2-pentyloxy group, 4-methyl- 2-pentyloxy group, 2-methyl-3-pentyloxy group, 3-methyl-3-pentyloxy group, 2,3-dimethyl-1-butyloxy group, 3,3-dimethyl-1-butyloxy group, 2,2-dimethyl-1-butyloxy group, 2-ethyl-1-butyloxy group, 3,3-dimethyl-2-butyloxy group and 2,3-dimethyl-2-butyloxy group.

As used herein, the term “C _1-6 alkylthio group” refers to a thio group bonded to a “C _1-6 alkyl group” as defined above, and in particular includes methylthio group, ethylthio group, 1-propylthio group, 2-propylthio group, butylthio group, and pentylthio group.

As used here, the expression "C _2-7 alkoxycarbonyl group" refers to a carbonyl group associated with a "C _1-6 alkoxy group" above, and in particular includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a 1-propyloxycarbonyl group and a 2-propyloxycarbonyl group.

As used here, the expression "C _2-7 alkylcarbonyl group" refers to the carbonyl group associated with the "C _1-6 alkyl group" above, and, in particular, includes, for example, methylcarbonyl group, ethylcarbonyl group, 1-propylcarbonyl a group and a 2-propylcarbonyl group.

As used herein, the term “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

As used here, the expression "C _6-10 aryl group" refers to an aromatic cyclic hydrocarbon group containing 6-10 carbon atoms, and, in particular, includes, for example, a phenyl group, a 1-naphthyl group and a 2-naphthyl group.

As used herein, the term “heteroatom” refers to a sulfur atom, an oxygen atom, and a nitrogen atom.

As used here, the expression "5-10 membered heteroaryl ring" refers to an aromatic 5-10 membered ring containing one or more heteroatoms, and, in particular, include, for example, a pyridine ring, a thiophene ring, a furan ring, a pyrrole ring , oxazole ring, isoxazole ring, thiazole ring, thiadiazole ring, isothiazole ring, imidazole ring, triazole ring, pyrazole ring, furazan ring, thiadiazole ring, oxadiazole ring, pyridazine ring, pyrimidine ring ring, pyrazine ring, triazine ring, indole ring, isoindole ring, indazole ring, chromene ring, quinoline ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring, naphthyridine ring, phthalazine ring, purine ring, pteridine ring imidazothiazole ring, benzofuran ring, benzothiophene ring, benzoxazole ring, benzothiazole ring, benzothiadiazole ring, benzimidazole ring, imidazopyridine ring ring, pyrrolopyridine ring, pyrrolopyrimidine ring and pyridopyrimidine ring. Preferably, the “5-10 membered heteroaryl ring” includes a pyridine ring, a thiophene ring, a furan ring, a pyrrole ring, an imidazole ring, a 1,2,4-triazole ring, a thiazole ring, a thiadiazole ring, a pyrazole ring, a furazan ring, a thiadiazole ring, pyridazine ring, pyrimidine ring, pyrazine ring, isoquinoline ring, benzoxazole ring, benzothiazole ring and benzimidazole ring. The most preferred example is a pyridine ring.

As used here, the expression "5-10 membered heteroaryl group" refers to a monovalent or divalent group resulting from the removal of one or two any hydrogen atoms from the "5-10 membered heteroaryl ring" above.

As used here, the expression “4-8 membered heterocyclic ring” refers to a non-aromatic ring in which

(i) the number of atoms making up the ring is 4-8;

(ii) the atoms that make up the ring include 1-2 heteroatoms;

(iii) the ring may contain 1-2 double bonds;

(iv) the ring may contain 1-3 carbonyl groups and

(v) the ring is monocyclic.

In particular, the 4-8 membered heterocyclic ring includes an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepane ring, an azocane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a thiazolidine ring, a thiazolidine ring a thiazoline ring and a ring represented by one of the following formulas:

(where s is an integer from 1 to 3; T ^3x represents a methylene group, an oxygen atom or a group represented by the formula —NT ^4x -, where T ^4x represents a hydrogen atom or a C _1-6 alkyl group. Preferably, “4- 8-membered heterocyclic rings include a pyrrolidine ring, a piperidine ring, an azepane ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a dihydrofuran-2-one ring and a thiazolidine ring.

As used here, the expression “4-8 membered heterocyclic group” refers to a monovalent or divalent group resulting from the removal of one or two hydrogen atoms from a “4-8 membered heterocycle” having the above meanings. Preferred “4-8 membered heterocyclic groups” include a piperidin-1-yl group, a pyrrolidin-1-yl group and a morpholin-4-yl group.

As used here, the expression "C _6-10 aryl C _1-6 alkyl group" refers to a group obtained by substituting an arbitrary hydrogen atom in one of the above "C _1-6 alkyl groups" of a "C _6-10 aryl group" having the above values, and, in particular, includes, for example, a benzyl group, a phenethyl group and a 3-phenyl-1-propyl group.

As used here, the expression “5-10 membered heteroaryl C _1-6 alkyl group” refers to the group obtained by substitution of a “5-10 membered heteroaryl group” having the above meanings, an arbitrary hydrogen atom “C _1-6 alkyl groups ", And, in particular, includes, for example, a 2-pyridylmethyl and 2-thienylmethyl group.

As used here, the expression “4-8 membered heterocyclyl C _1-6 alkyl group” refers to the group obtained by replacing an arbitrary hydrogen atom in the “C _1-6 alkyl group” with a “4-8 membered heterocyclic group” having the above values.

As used here, the expression "monocyclic or bicyclic 4-12 membered heterocyclic group containing one or two nitrogen atoms in the ring, which may have one or more substituents" refers to a non-aromatic cyclic group, which may have one or more substituents. In such non-aromatic cyclic groups

(i) the number of atoms making up the ring of the cyclic group is 4-12;

(ii) the atoms that make up the ring of the cyclic group include one or two nitrogen atoms and

(iii) the group has a monocyclic or bicyclic structure.

Specific examples of such groups correspond to the following formulas:

(where n and m, each independently, are 0 or 1; R ³¹ to R ⁴⁴ , each independently, are a hydrogen atom or a substituent selected from those referred to by the phrase “which may have one or more substituents” (substituents of the specified further S); any two radicals from R ³¹ -R ⁴⁴ may together form a C _1-6 alkylene group).

Used in the text, the expression "which may have one or more substituents" means that the group in question may contain one or more substituents in any combination in a substitutable position. Examples of such substituents are those selected from the following substituent group S.

<Deputy group S>

This group includes:

(1) a halogen atom,

(2) a hydroxyl group,

(3) mercapto group,

(4) a nitro group,

(5) a cyano group,

(6) a formyl group,

(7) a carboxyl group,

(8) a trifluoromethyl group,

(9) trifluoromethoxy group,

(10) an amino group,

(11) oxo group,

(12) an imino group, and

a group represented by the formula —T ^1x —T ^2x (where T ^1x represents a single bond, a C _1-6 alkylene group, an oxygen atom, a group represented by the formula —CO—, a group represented by the formula —S—, a group represented by the formula - S (O) -, a group represented by —S (O) ₂ -, a group represented by —O — CO—, a group represented by —CO — O—, a group represented by —NR ^T -, a group represented by by the formula —CO — NR ^T -, a group represented by the formula NR ^T —CO—, a group represented by the formula —SO ₂ —NR ^T -, a group represented by the formula —N R ^T —SO ₂ -, a group represented by the formula —NH — CO — NR ^T - or a group represented by the formula —NH — CS — NR ^T -;

T ^2x represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, 5- A 10 membered heteroaryl group or a 4-8 membered heterocyclic group;

R ^T represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group,

provided that T ^2x and R ^T , each independently, may have 1-3 substituents selected from the following substituent groups T).

<Deputy group T>

This group includes hydroxyl, cyano, halogen atom, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, phenyl, 1-naphthyl, 2-naphthyl, 5-10 membered heteroaryl A 4-8 membered heterocyclic ring, C _1-6 alkoxy, C _1-6 alkylthio, C _2-7 alkoxycarbonyl group, etc.

<Deputy group S>

Preferably includes

(1) a halogen atom,

(2) a hydroxyl group,

(3) a cyano group,

(4) a carboxyl group,

(5) a trifluoromethyl group,

(6) trifluoromethoxy group,

(7) an amino group,

(8) a C _1-6 alkyl group,

(9) a C _3-8 cycloalkyl group,

(10) a C _2-6 alkenyl group,

(11) a C _2-6 alkynyl group,

(12) a phenyl group and

(13) C _1-6 alkoxy.

As used here, the term "group represented by the formula

(where n and m, each independently, are 0 or 1), which may contain one or more substituents "refers to a group represented by the formula

(where R ³¹ -R ⁴⁴ independently represent a hydrogen atom or a group selected from the substituents related to the phrase “which may have one or more substituents” above (a group of substituents S is defined above); n and m each independently represent itself 0 or 1). Preferably, when m = n = 0. More preferably, when the term refers to a group represented by one of the formulas

(where R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ independently represent a hydrogen atom or a group selected from groups of substituents related to the phrase “which may have one or more substituents” (substituent group S is defined above), when provided that at least three of R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are hydrogen atoms, even more preferably when the term refers to a group represented by one of the formulas

Most preferably, when the term refers to a group represented by the formula

As used here, the term "group represented by the formula

(where n and m, each independently, are 0 or 1) "refers to the group represented by one of the formulas

As used herein, the term “piperidin-1-yl group which may have one or more substituents” refers to a “piperidin-1-yl group” which may have one or more substituents at substitutable positions selected from the group by which is referred to by the phrase “which may contain one or more substituents (the above group of substituents S). A preferred term “piperidin-1-yl group which may have one or more substituents” refers to a group of the following formula:

(where R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ each independently represent a hydrogen atom or a group selected from substituents referred to in the phrase “which may have one or more substituents” (the above group of substituents S), provided that at least three radicals from R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ are hydrogen atoms, preferably when the term in question refers to a group corresponding to one of the following formulas:

Even more preferably, when the term in question refers to a group corresponding to one of the following formulas:

As used here, the expression "azetidin-1-ilen group, which may have one or more substituents" refers to "azetidin-1-ilen group", which may have one or more substituents in substitutable positions selected from the group, by which is referred to by the expression "which may contain one or more substituents (the above group of substituents S).

As used here, the expression "pyrrolidin-1-yl group that may have one or more substituents" refers to a "pyrrolidin-1-yl group" which may have one or more substituents at substitutable positions selected from the group by which is referred to by the expression "which may contain one or more substituents."

As used herein, the expression “piperidin-1-yl group which may have one or more substituents” refers to a “piperidin-1-yl group” which may have one or more substituents at substitutable positions selected from the group by which is referred to by the expression "which may contain one or more substituents."

As used herein, the expression “azepan-1-yl group which may have one or more substituents” refers to a “azepan-1-yl group” which may have one or more substituents at substitutable positions selected from the group by which is referred to by the expression "which may contain one or more substituents."

As used herein, the expression “piperidin-1-yl group which may contain an amino group” refers to a “piperidin-1-yl group” which may contain an amino group in a substitutable position. The specific meaning of the expression “piperidin-1-yl group which may contain an amino group” refers to a group represented by one of the following formulas:

preferably to the group represented by one of the formulas

As used here, the expression "azetidin-1-ilen group, which may contain an amino group" refers to "azetidin-1-ilen group", which may contain an amino group in a substitutable position.

As used herein, the expression “pyrrolidin-1-yl group which may contain an amino group” refers to a “pyrrolidin-1-yl group” which may contain an amino group in a substitutable position.

As used herein, the expression “piperidin-1-yl group which may contain an amino group” refers to a “piperidin-1-yl group” which may contain an amino group in a substitutable position.

As used herein, the expression “azepan-1-yl group which may contain an amino group” refers to “azepan-1-yl group” which may contain an amino group in a substitutable position.

As used here, the expression "C _1-6 alkyl group which may have one or more substituents" in the above substituents of group B refers to a "C _1-6 alkyl group" which may have one or more substituents in substitutable positions selected from those referred to by the expression "which may have one or more substituents." The preferred term “C _1-6 alkyl group which may have one or more substituents” refers to a C _1-6 alkyl group which may have one or two substituents selected from the group consisting of a cyano group, a carboxyl group, C _2-7 alkoxycarbonyl group, a group represented by the formula —NR ^3T COR ^4T , a group represented by the formula —CONR ^3T R ^4T (where R ^3T and R ^4T each independently represents a hydrogen atom or a C _1-6 alkyl group) and C _1-6 alkoxy groups.

In the compound represented by the above formula (I), R ¹ and R ² each independently represent a group represented by the formula -A ⁰ -A ¹ -A ² (where A ⁰ , A ¹ and A ² have the above meanings) , in the case when each of A ⁰ and A ¹ represents a single bond, “-A ⁰ -A ¹ -“ represents a single bond.

Used in relation to the above formula (I), the expression "when Z ² represents a group represented by the formula -CR ² =, R ¹ and R ² can together form a 5-7 membered ring" means that the compounds corresponding to the above formula ( I) include compounds (II) represented by the following formula:

(where Z ¹ , X and T ¹ have the above meanings; A ^T1 represents an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a methylene group which may have one or more substituents, or a nitrogen atom which may have one or more substituents; A ^T2 is a C _2-6 alkylene group which may have one or more substituents). In the above formula (II), A ^{T1 is} preferably an oxygen atom, and A ^{T2 is} preferably a C _2-4 alkylene group.

As used here, the expression "cyanobenzyl group" refers to a benzyl group containing one cyano group, and, in particular, includes, for example, a 2-cyanobenzyl group, a 3-cyanobenzyl group and a 4-cyanobenzyl group.

As used herein, the term “fluorocyanobenzyl group” refers to a benzyl group substituted by a fluorine atom and a cyano group, and in particular includes, for example, a 2-cyano-4-fluorobenzyl group and a 2-cyano-6-fluorobenzyl group.

As used herein, the term “carbamoylphenoxy group” refers to a phenoxy group containing a substituent of the formula —CONH ₂ , exemplified by the 2-carbamoylphenoxy group, the 3-carbamoylphenoxy group, and the 4-carbamoylphenoxy group.

As used here, the expression “salts” is not restrictive if such salts are pharmaceutically applicable substances and derivatives of any compound of the present invention. Examples of the salts in question are salts of inorganic acids, salts of organic acids, salts of inorganic bases, salts of organic bases and salts of acidic or basic amino acids.

Examples of preferred inorganic salts include hydrochloride, hydrobromide, sulfate, nitrate and phosphate. Preferred organic salts include acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate and p-toluenesulfonate.

Examples of preferred salts of inorganic bases include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; aluminum salts and ammonium salts. Preferred examples of organic base salts include diethylamine salts, diethanolamine salts, meglumine salts, and N, N'-dibenzylethylenediamine salts.

Examples of preferred acidic acid salts of amino acids include aspartate and glutamate. Examples of preferred basic amino acid salts include arginine salts, lysine salts and ornithine salts.

The present invention provides compounds corresponding to the following formula (I), its salts or hydrates thereof:

where T ¹ represents a monocyclic or bicyclic 4-12-membered heterocyclic group containing one or two ring nitrogen atoms, and may have one or more substituents;

X represents a C _1-6 alkyl group which may have one or more substituents, a C _2-6 alkenyl group which may have one or more substituents, a C _2-6 alkynyl group which may have one or more substituents, C _{6 A -10} aryl group which may have one or more substituents, a 5-10 membered heteroaryl group which may have one or more substituents, a C _6-10 aryl C _1-6 alkyl group which may have one or more substituents, or 5-10 membered heteroaryl C _1-6 alkyl group which may have one or more substituents;

Z ¹ and Z ² each independently represent a nitrogen atom or a group represented by the formula —CR ² =;

R ¹ and R ² each independently represent a group represented by the formula —A ⁰ —A ¹ —A ²

(where A ⁰ is a single bond or a C _1-6 alkylene group which may have 1-3 substituents selected from the following substituent group B;

And ¹ represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O — CO—, a group represented by the formula —CO — O—, a group represented by the formula —NR ^A - , a group represented by the formula —CO — NR ^A -, a group represented by the formula —NR ^A —CO—, a group represented by the formula —SO ₂ —NR ^A -, or a group represented by the formula —NR ^A —SO ₂ -;

A ² and R ^A each independently represent a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{6- 10} aryl group, 5-10 membered heteroaryl group, 4-8 membered heterocyclic group, 5-10 membered heteroaryl C _1-6 alkyl group, C _6-10 aryl C _1-6 alkyl group or C _2-7 alkylcarbonyl a group, provided that A ² and R ^A each independently have 1-3 substituents selected from the following substituent group B).

In the case where Z ² represents a group represented by the formula —CR ² =, R ¹ and R ² can together form a 5-7 membered ring.

This excludes cases where [1] R ¹ represents a hydrogen atom; Z ¹ represents a nitrogen atom, and Z ² represents —CH =; [2] Z ¹ represents a nitrogen atom, and Z ² represents a group —C (OH) =.

<Deputy group B>

Substituent group B includes a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C _1-6 alkyl group which may have one or more substituents, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, C _{2 -6} alkynyl group, C _6-10 aryl group, 5-10 membered heteroaryl group, 4-8 membered heterocyclic group, C _1-6 alkoxy group, C _1-6 alkylthio group, a group represented by the formula —SO ₂ —NR ^B1 -R ^B2 , a group represented by the formula -NR ^B1 -CO-R ^B2 , a group represented by the formula -NR ^B1 -R ^B2 (where R ^B1 and R ^B2 each independently represent a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^B3 (in which R ^B3 represents a 4-8 membered heterocyclic group), a group represented by the formula —CO — R ^B4 —R ^B5 and a group represented by the formula —CH ₂ —CO — R ^B4 —R ^B5 (in which R ^B4 represents a single bond, an oxygen atom or a group represented by the formula NR ^B6 -; R ^B5 and R ^B6 each independently represent a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, 5 A 10-membered heteroaryl group, a 4-8 heterocyclic C _1-6 alkyl group, a C _6-10 aryl C _1-6 alkyl group, or a 5-10 membered heteroaryl C _1-6 alkyl group).

Preferred compounds represented by formula (I) include, for example, the following compounds:

(1) compounds in which any, but not both of the radicals Z ¹ and Z ² represents a nitrogen atom;

(2) compounds in which Z ¹ represents a nitrogen atom; Z ² represents a group represented by the formula —CR ² = (wherein R ² is as defined above for R ² );

(3) compounds in which Z ² represents a nitrogen atom; Z ¹ represents a group represented by the formula —CR ² = (wherein R ² is as defined above for R ² );

(4) compounds in which T ¹ is a group which may have one or more substituents and is represented by the formula

(where n and m are each independently 0 or 1), an azetidin-1-yl group which may have one or more substituents, a pyrrolidin-1-yl group which may have one or more substituents, piperidin-1-yl a group which may have one or more substituents or an azepan-1-yl group which may have one or more substituents;

(5) compounds in which T ¹ is a group represented by the formula

(where n and m are each independently 0 or 1), an azetidin-1-yl group which may contain an amino group, a pyrolidin-1-yl group which may contain an amino group, a piperidin-1-yl group which may contain an amino group or an azepan-1-yl group which may contain an amino group;

(6) compounds in which T ¹ represents a piperazin-1-yl group or a 3-aminopiperidin-1-yl group;

(7) compounds in which T ¹ represents a piperazin-1-yl group;

(8) compounds in which X represents a group represented by the formula —X ¹ —X ² (wherein X ¹ represents a single bond or a methylene group which may have one or more substituents; X ² represents a C _2-6 alkenyl group which may have one or more substituents; a C _2-6 alkynyl group which may have one or more substituents or a phenyl group which may have one or more substituents);

(9) compounds in which X represents a group represented by the formula —X ¹¹ —X ¹² (wherein X ¹¹ represents a single bond or a methylene group; X ¹² represents a C _2-6 alkenyl group, a C _2-6 alkynyl group, or a phenyl group which may have one or more substituents);

(10) compounds in which a phenyl group which may contain one or more substituents included in X represented by a group of the formula —X ¹¹ —X ¹² is a phenyl group which may contain in position 2 a substituent selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a vinyl group, a methoxy group, an ethoxy group, an acetyl group, a cyano group, a formyl group, and a C _2-7 alkoxycarbonyl group;

(11) compounds in which X represents a 3-methyl-2-buten-1-yl group, a 2-butyn-1-yl group, a benzyl group, or a 2-chlorophenyl group;

(12) compounds in which X represents a 2-butyn-1-yl group;

(13) compounds in which R ¹ represents a hydrogen atom or a group represented by the formula —A ¹⁰ —A ¹¹ —A ¹² ,

where A ¹⁰ represents a C _1-6 alkylene group, which may contain 1-3 substituents selected from the following substituent group C;

A ¹¹ represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group;

A ¹² represents a hydrogen atom, a C _6-10 aryl group which may have 1-3 substituents selected from the following substituent group C, a 5-10 membered heteroaryl group which may have 1-3 substituents selected from the following substituent groups C, a 5-10 membered heteroaryl C _1-6 alkyl group which may have 1-3 substituents selected from the following substituent group C, or a C _6-10 aryl C _1-6 alkyl group which may have 1 -3 substituents selected from the following substituent group C.

<Deputy group C>

The substituent group C represents a group containing a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR ^C1 —R ^C2 (where R ^C1 and R ^C2 each independently represents a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^C3 —R ^C4 , and a group represented by the formula —CH ₂ —CO — R ^C3 —R ^C4 (where R ^C3 is a single bond, an oxygen atom, a group represented by the formula —NR ^C5 -; R ^C4 and R ^C5 , each n independently represent a hydrogen atom or a C _1-6 alkyl group);

(14) compounds in which R ¹ represents a hydrogen atom, a C _1-6 alkyl group, which may have 1-3 substituents selected from the following substituent group C, a 5-10 membered heteroaryl C _1-6 alkyl group, which may have 1-3 substituents selected from the following substituent group C, or a C _6-10 aryl C _1-6 alkyl group, which may have 1-3 substituents selected from the following substituent group C;

<Deputy group C>

The substituent group C represents a group containing a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR ^C1 —R ^C2 (where R ^C1 and R ^C2 each independently represent a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^C3 —R ^C4 and a group represented by the formula —CH ₂ —CO — R ^C3 - R ^C4 (where R ^C3 represents a single bond, an oxygen atom, a group represented by the formula —NR ^C5 -; R ^C4 and R ^C5 , each not depending on a hydrogen atom or a C _1-6 alkyl group);

(15) compounds in which the above substituent group C for the group represented by formula A ¹⁰ -A ¹¹ -A ¹² represented by the radical R ¹ includes a cyano group, a C _1-6 alkoxy group, a C _2-7 alkoxycarbonyl group and a halogen atom;

(16) compounds in which R ¹ represents a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a 2-methoxyethyl group or a 4-methoxycarbonylpyridin-2-yl group;

(17) compounds in which R ¹ represents a methyl group or a 2-cyanobenzyl group;

(18) compounds in which R ² represents a hydrogen atom, a cyano group or a group represented by the formula —A ²¹ —A ²² ,

where A ²¹ represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O — CO—, a group represented by the formula —CO — O—, a group represented by the formula —NR ^A2 -, a group represented by the formula —CO — NR ^A2 -, or a group represented by the formula —NR ^A2 —CO—;

A ²² and R ^A2 each independently represent a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group A 5-10 membered heteroaryl group, a 4-8 membered heterocyclic group, a 5-10 membered heteroaryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkyl group, with the proviso that A ²² and R ^A2 , each independently, may contain 1-3 substituents selected from the following substituent group D;

<Deputy group D>

The substituent group D is a group containing a hydroxyl group, a cyano group, a nitro group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR ^D1 —R ^D2 (where from R ^D1 and R ^D2 each independently represents a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^D3 (where R ^D3 represents a 4-8 membered heterocyclic group), and a group represented by the formula —CO — R ^D4 —R ^D5 (wherein R ^D4 is a single bond, an oxygen atom an ode or a group represented by the formula —NR ^D6 -; R ^D5 and R ^D6 each independently represents a hydrogen atom, a C _3-8 cycloalkyl group or a C _1-6 alkyl group);

(19) a compound in which R ² represents a hydrogen atom, a cyano group, a carboxy group, a C _2-7 alkoxycarbonyl group, a C _1-6 alkyl group, a group represented by the formula —CONR ^D7 R ^D8 (where R ^D7 and R ^D8 each independently represent a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula -A ²³ -A ²⁴ (where A ²³ represents an oxygen atom, a sulfur atom or a group represented by the formula -NR ^A3 -; A ²⁴ and R ^A3, each independently represent a hydrogen atom, a C _1-6 alkyl group which may have a substituent selected from yk D1 bound more substituent group, _C3-8 cycloalkyl group which may have a substituent selected from Group D1 of said further substituents, C _2-6 alkenyl group which may have a substituent selected from Group D1 of said further substituents, C _2-6 an alkynyl group which may have a substituent selected from the following substituent group D1, a phenyl group which may have a substituent selected from the following substituent group D1, or a 5-10 membered heteroaryl group which may have a substituent, abusive from said further substituent group D1.

<Deputy group D1>

The substituent group D1 is a group consisting of a carboxy group, a C _2-7 alkoxycarbonyl group, a C _1-6 alkyl group, a group represented by the formula —CONR ^D7 R ^D8 (where R ^D7 and R ^D8 each independently represent a hydrogen atom or C _1-6 alkyl group), a pyrrolidine-1-carbonyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group;

(20) compounds in which R ² represents a hydrogen atom, a cyano group, a C _1-6 alkoxy group or a group represented by the formula -A ²⁵ -A ²⁶ (where A ²⁵ represents an oxygen atom, a sulfur atom, a group represented by the formula -NR ^A4 -; A ²⁶ and R ^A4 each independently represent a hydrogen atom, a C _1-6 alkyl group having a substituent selected from the following substituent group D1, a C _3-8 cycloalkyl group having a substituent selected from the following group substituents D1, or a phenyl group having a substituent selected from bound group D further substituents;

<Deputy group D1>

The substituent group D1 is a group consisting of a carboxyl group, a C _2-7 alkoxycarbonyl group, a C _1-6 alkyl group, a group represented by the formula —CONR ^D7 R ^D8 (where R ^D7 and R ^D8 each independently represent a hydrogen atom or a C _1-6 alkyl group), a pyrrolidin-1-ylcarbonyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group;

(21) compounds in which R ² represents a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group, a group represented by one of the following formulas:

(where A ²⁷ represents an oxygen atom, a sulfur atom or a group represented by the formula —NH—;

A ²⁸ and A ²⁹ each independently represent a hydrogen atom or a C _1-6 alkyl group);

(22) compounds in which R ² represents a hydrogen atom, a cyano group or a carbamoylphenyloxy group.

Of the above compounds, the preferred values of Z ¹ and Z ² are compounds (1) to (3), of which (3) is most preferred; preferred in terms of T ¹ are compounds (4) to (7), of which (7) is most preferred; preferred in terms of X are compounds (8) to (12), of which (12) is most preferred; preferred in terms of R ¹ are compounds (13) to (17), of which (17) is most preferred; preferred in terms of R ² are compounds (18) to (22), of which (22) is most preferred.

Preferred compounds of the above formula (I) correspond to any embodiments 2-5 selected from the groups including compounds (1) - (3), (4) - (7), (8) - (12), (13) - ( 17) and (18) - (22).

Examples of preferred compounds are substances with the following special combination of embodiments:

(i) compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (1), (4), (8), (13 ) and (18), respectively;

(ii) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (2), (6), (11), (16 ) and (19), respectively;

(iii) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (2), (6), (11), (16 ) and (20), respectively;

(iv) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (2), (6), (11), (16 ) and (21), respectively;

(v) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (2), (6), (11), (16 ) and (22), respectively;

(vi) compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (2), (6), (12), (17 ) and (19), respectively;

(vii) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (2), (6), (12), (17 ) and (20), respectively;

(viii) compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings given in the above items (2), (6), (12), (17 ) and (21), respectively;

(ix) the compounds represented by the above formula (I) in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings given in the above (2), (6), (12), (17) ) and (22), respectively;

(x) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (3), (6), (11), (16 ) and (19), respectively;

(xi) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (3), (6), (11), (16 ) and (20), respectively;

(xii) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² are as defined above (3), (6), (11), (16 ) and (21), respectively;

(xiii) the compounds represented by the above formula (I) in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings given in the above items (3), (6), (11), (16 ) and (22), respectively;

(xiv) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (3), (6), (12), (17 ) and (19), respectively;

(xv) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² are as defined above (3), (6), (12), (17) ) and (20), respectively;

(xvi) the compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings of the above items (3), (6), (12), (17 ) and (21), respectively;

(xvii) compounds represented by the above formula (I), in which Z ¹ and Z ² , T ¹ , X, R ¹ and R ² have the meanings given in the above items (3), (6), (12), (17 ) and (22), respectively.

In the above list, for compounds (ii) - (ix), the preference of compounds increases in sequence from (ii) to (ix) and for compounds (x) - (xvii) from (x) to (xvii).

The following table provides specific examples of compounds of formula (I), not limiting the scope of the invention.

The abbreviations used in the table have the following meanings:

P1 is piperazin-1-yl; P2 is 3-aminopiperidin-1-yl; 2Btyn - 2-butyn-1-yl; 3Me2Bten - 3-methyl-2-buten-1-yl; Me is methyl; Et is ethyl; 2-CNBen - 2-cyanobenzyl; 6F2CNBen - 6-fluoro-2-cyanobenzyl; phenethyl-2-phenylethyl; 2Ph20xEt - 2-phenyl-2-oxoethyl; -CR2 =, -CR ² =.

Among the above compounds, compounds with the numbers 1, 2, 4, 6, 7, 8, 10, 13, 16, 41, 42, 44, 50, 53, 81, 85, 86, 87, 111, 141 and 183 are preferred and compounds 2, 4, 8, 10, 81, 87 and 111 are particularly preferred.

<Typical Synthesis Methods>

Typical processes for preparing the compounds represented by the above formula (I) are described below.

The following is a definition for each character used in production methods. R ³¹ -R ⁴² , n, m, R ¹ , R ² , X, A ⁰ , A ¹ , A ² , R ^A and T ¹ have the above meanings.

U ¹ and U ³ each independently represent a leaving group, such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group.

R ^p1 , R ^p2 and R ^p3 each independently represent an NH-protecting group, for example a pivaliloxymethyl group and a trimethylsilylethoxymethyl group.

R ^p4 represents a hydroxy protecting group such as a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group.

R ^p5 represents an NH-protecting group such as N, N-dimethylsulfamoyl, trityl, benzyl and tert-butoxycarbonyl.

U ² and U ⁴ each independently represent a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a group represented by the formula —B (OH) ₂ , 4,4,5,5-tetramethyl-1,3 , 2-dioxaboran-2-yl group or a group represented by the formula —Sn (R ^z ) ₃ (where R ^z represents a C _1-6 alkyl group).

R ^x2 is a group represented by the formula —O — A ^x , a group represented by the formula —SA ² , a group represented by the formula —N (R ^A ) A ² or a 4-8 membered heterocyclic group which may have one or more substituents ( e.g. 1-pyrrolidinyl, 1-morpholinyl, 1-piperazinyl or 1-piperidyl) and the like.

R ^x3 is a group represented by the formula —A ⁰ —A ¹ —A ² -, such as a cyano group, a C _1-6 alkyl group which may have one or more substituents, a C _3-8 cycloalkyl group which may have one or more substituents, a C _2-6 alkenyl group which may have one or more substituents, a C _2-6 alkynyl group which may have one or more substituents, and a C _6-10 aryl group which may have one or more substituents.

A ^2COOR represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, a 5-10 membered heteroaryl group, 4-8 a membered heterocyclic group, a 5-10 membered heteroaryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkyl group, each of which contains an ether group.

A ^2COOH represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, a 5-10 membered heteroaryl group, 4-8 a membered heterocyclic group, a 5-10 membered heteroaryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkyl group, each of which contains a carboxyl group.

A ^2NO2 represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, a 5-10 membered heteroaryl group, 4-8 a membered heterocyclic group, a 5-10 membered heteroaryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkyl group, each of which contains a nitro group.

A ^2NH2 represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, a 5-10 membered heteroaryl group, 4-8 a membered heterocyclic group, a 5-10 membered heteroaryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkyl group, each of which contains an amino group.

A ^2CN represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, a 5-10 membered heteroaryl group, 4-8 a membered heterocyclic group, a 5-10 membered heteroaryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkyl group, each of which contains a nitrile group.

A ^CONH2 represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, a 5-10 membered heteroaryl group, 4-8 a membered heterocyclic group, a 5-10 membered heteroaryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkyl group, each of which contains a carboxamide group.

M represents — MgCl, — MgBr, —Sn (R ^z ) ₃ (where R ^z is as defined above), and the like.

The term "room temperature" refers to a temperature in the range of 20-30ºC.

T ^{1a is} defined as a group of the formula T ¹ , or is a group of the formula

a group of formula

(where R ³¹ -R ⁴⁴ have the above meanings, unless any of R ³¹ -R ⁴⁴ is —NH-R ^p3 ) or a group of the formula

(where R ³¹ -R ⁴⁰ have the above meanings, unless any of R ³¹ -R ⁴⁰ is —NH-R ^p3 ).

Unless otherwise indicated, in the examples of reactions represented by the following schemes, the amounts of reagents, catalysts, etc. used (equivalents, wt.% And mass ratios) are calculated on the basis of the basic substance for each reaction scheme. The term "basic substance" refers to a compound depicted by the chemical formula in the reaction scheme and having the structure of the compounds of the present invention.

The method of obtaining a

[Stage A1]

At this stage, the —NH-protecting reagent is reacted with compound (1a) [CAS No. 56160-64-6] to give compound (2a). The reaction conditions are selected depending on the type of -NH-protective reagent used. The reaction can be carried out under conditions that are commonly used to introduce a protecting group using an appropriate reagent.

The term “-NH-protective reagent” refers to a reagent that is commonly used to introduce an N-protective group. Examples of such -NH-protective reagents include chloromethyl pivalate. It is preferable to use 1-2 equivalents of a protective reagent. Examples of solvents that can be used in the reaction under consideration are acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran and dimethoxyethane. N, N-dimethylformamide is preferably used.

The reaction may be carried out in the presence of a base. Examples of bases used in the reaction under consideration are cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate and sodium hydride. Sodium hydride is preferred. In this case, the preferred amount of base is 1-5 equivalents. The reaction can be carried out at a temperature of 0-150ºС. It is preferable to use room temperature.

[Stage A2]

In this step, compound (2a) is reacted with compound (2a-2) to give compound (3a).

As the compound (2a-2), any compound representing an electrophilic reagent, for example, an alkyl halide, can be used. Specific examples of halide alkyls include iodomethane, iodoethane, iodopropane, and benzyl bromide; alkenyl halides such as allyl bromide and 1-bromo-3-methyl-2-butene; and alkynyl halides such as propargyl bromide and 1-bromo-2-butine. It is preferable to use 1-2 equivalents of an electrophilic reagent.

As solvents for this reaction, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran and toluene can be used.

The reaction can be carried out in the presence or absence of a base. Examples of bases used are lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, butyllithium, methyl lithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) ) amide and potassium bis (trimethylsilyl) amide. In this case, it is preferable to use one to two equivalents of the base.

The reaction can be carried out at a temperature of 0-150ºС.

[Stage A3]

At this stage, the benzyl group is removed from position 7 of compound (3a) to give compound (4a).

Compound (4a) can be obtained, for example, by catalytic reduction of compound (3a) in a hydrogen atmosphere in the presence of a metal catalyst, however, the reaction conditions are not limited to the above.

Specific solvents for carrying out such a reaction include methanol, ethanol, propanol, acetic acid, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran and toluene. Examples of metal catalysts include palladium on carbon, platinum oxide, and Raney nickel. It is preferable to use 0.5-50 wt.% The catalyst. The preferred hydrogen pressure is 1-5 atm. The reaction can be carried out at a temperature of 0-150ºС.

[Stage A4]

In this step, compound (4a) is reacted with compound (4a-2) to give compound (5a).

Specific examples of compound (4a-2) are alkyl halides such as iodomethane, iodoethane, iodopropane, and benzyl bromide; alkenyl halides such as allyl bromide and 1-bromo-3-methyl-2-butene; or alkynyl halides such as propargyl bromide and 1-bromo-2-butine. These halides are preferably used in an amount of 1-2 equivalents.

Solvents for this reaction include dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran and toluene.

The reaction can be carried out in the presence or absence of a base. Examples of bases used to carry out such a reaction are lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, butyl lithium, methyl lithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide. In this case, it is preferable to use 1-4 equivalents of base. The reaction can be carried out at a temperature of 0-150ºС.

Compound (5a) can be obtained by reacting compound (4a) with compound (4a-2) in the presence of a copper catalyst and a base. In this case, it is preferable to use 0.1-2 equivalents of copper catalyst and 1-10 equivalents of base.

Compound (4a-2) may be arylboronic acid, heteroarylboronic acid in which X represents a C _6-10 aryl group which may have one or more substituents, or a 5-10 membered heteroaryl group which may have one or more substituents, and U ² represents —B (OH) ₂ . It is preferable to use one to three equivalents of compound (4a-2).

The reaction can be carried out in the presence of solvents such as dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, pyridine, N, N-dimethylformamide and N-methylpyrrolidone.

Bases include triethylamine, diisopropylethylamine, pyridine and N, N-dimethylaminopyridine. Copper catalysts can be copper (II) acetate, copper (II) trifluoroacetate, copper (II) chloride and copper (II) iodide. The reaction can be carried out at temperatures of 0-150ºС.

[Stage A5]

In this step, compound (5a) is reacted with a halogenating agent to give compound (6a).

Specific examples of halogenating agents include N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide. The halogenating agent is preferably used in an amount of 1-4 equivalents.

As solvents for the reaction in question, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran and dimethoxyethane can be used. The reaction can be carried out at a temperature of 0-150ºС.

[Stage A6]

In this step, compound (6a) is reacted with compound (7a) to give compound (8a). In this case, it is preferable to use 1-4 equivalents of compound (7a).

The reaction can be carried out in solvents such as tetrahydrofuran, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, 1,4-dioxane, toluene and xylene, or in the absence of a solvent. The reaction can be carried out at a temperature of 0-200 ° C in the presence or absence of a base. Examples of bases are triethylamine, potassium carbonate and 1,8-diazabicyclo [5.4.0] undecene. In the present case, it is preferable to use 1-4 equivalents of base.

[Stage A7]

At this stage, the NH-protecting group is removed from position 3 of compound (8a) to give compound (9a). The reaction conditions are selected according to the type of N-protecting group to be removed. The deprotection reaction may be carried out under normal conditions.

So, for example, in the case when R ^p2 represents a pivaliloxymethyl group, the reaction is carried out in methanol or a mixture of methanol with tetrahydrofuran using sodium methylate, sodium hydride or 1,8-diazabicyclo [5.4.0] -7 as the base -undecene at a temperature of 0-150ºС. In this case, it is preferable to use 0.1 to 2 equivalents of base.

If R ^p2 is a trimethylsilylethoxymethyl group, the reaction can be carried out in a solvent such as acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran or dimethoxyethane, using a reagent such as tetrabutylammonium fluoride or cesium fluoride , at a temperature of 0-150ºС. In this case, it is preferable to use 1-5 equivalents of a fluoride reagent.

[Stage A8]

In this step, compound (9a) is chlorinated to give compound (10a).

There are no particular restrictions on the reaction conditions, and the reaction can be carried out under ordinary chlorination conditions. So, for example, the reaction can be carried out at a temperature of 0-150ºC in a solvent such as phosphorus oxychloride. In this case, it is preferable to use a 10-200-fold excess of the chlorinating agent.

In the case where R ^p3 is a tert-butoxycarbonyl group which is removed under the above conditions involving the use of phosphorus oxychloride, re-introduction of the protective group is required.

There are no particular restrictions on the conditions for the reaction to introduce the protective group. In the case of a tert-butoxycarbonyl group, the reaction can be carried out using a -NH-protective agent such as di-tert-butyl dicarbonate in a solvent such as acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran or dimethoxyethane, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate or triethylamine, at 0-150 ° C.

[Stage A9]

In this step, compound (11a) is reacted with compound (11a-2) to give compound (10a).

Compound (11a-2) includes alcohol derivatives or phenol derivatives represented by the general formula A ² —OH, amine derivatives represented by the general formula A ² (R ^A ) NH or the like, and thiol derivatives represented by the general formula A ² —SH. In this case, the compound (11a-2) is preferably used in an amount of 1-10 equivalents or in a 5-100-fold mass excess.

As solvents, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol and ethanol can be used.

The reaction can be carried out in the presence or absence of a base. The bases used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, butyllithium, methyl lithium, lithium bis (trimethylsilyl) amide, bis ( trimethylsilyl) sodium amide, potassium bis (trimethylsilyl) amide and triethylamine. In this case, it is preferable to use 1-10 equivalents of base. The reaction can be carried out at a temperature of 0-150ºС.

[Stage A10]

At this stage, the compound (10a) and the compound (13a) are reacted in the presence of a metal catalyst to produce the compound (12a). In this case, it is preferable to use 1-50 equivalents of compound (13a).

Solvents used include acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol and ethanol.

Metal catalysts include palladium and copper catalysts. Palladium catalysts include tetrakistriphenylphosphine palladium, palladium acetate and palladium dibenzylideneacetonate. The copper catalyst may be copper iodide. It is preferable to use 0.01-2 equivalents of a metal catalyst.

The reaction can be carried out in the presence of an organophosphorus ligand. When the reaction is carried out in the presence of an organophosphorus ligand, examples of ligands include o-tolylphosphine and diphenylphosphineferrocene. In this case, it is preferable to use 1-5 equivalents of an organophosphorus ligand relative to the amount of metal catalyst.

The reaction can be carried out in the presence or absence of a base. The bases used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, potassium phosphate, lithium bis (trimethylsilyl) amide, bis (trimethylsilyl) amide sodium, bis (trimethylsilyl) potassium amide and triethylamine. The reaction can be carried out at a temperature of 0-150ºС.

[Stage A11]

At this stage, the compound (10a) is reacted with a cyanidating reagent to produce the compound (14a).

Specific cyanidation reagents include, for example, sodium cyanide and potassium cyanide. They are preferably used in an amount of 1-20 equivalents.

Reaction solvents include, for example, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol and ethanol. The reaction can be carried out at a temperature of 0-150ºС.

[Stage A12]

At this stage, the cyano group of compound (14a) is hydrolyzed to give compound (15a). There are no special restrictions regarding the reaction conditions, and the reaction can be carried out under normal conditions of conversion of the cyano group to a carbamoyl group by hydrolysis.

Reaction solvents include acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, ethanol and a mixed solvent of tetrahydrofuran and methanol.

The reaction can be carried out in the presence or absence of a base. When using a base, the reaction can be carried out in the presence of an aqueous solution of a base such as potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia. The interaction can be achieved by adding an aqueous solution of hydrogen peroxide (preferably in the form of a 30% aqueous solution of hydrogen peroxide).

The reaction can be carried out at a temperature of 0-150ºС.

[Stage A13]

At this stage, R ^p3 is removed from compound (16a) to give compound (17a). As the compound (16a), compounds (11a), (12a), (14a), (15a) and other compounds can be used.

The deprotection reaction at R ^p3 can be carried out under normal conditions for the removal of -NH-protecting groups.

For example, when R ^p3 is a tert-butoxycarbonyl group, the reaction can be carried out in the presence of an acid, such as anhydrous methanol solution of hydrogen chloride, anhydrous ethanol solution of hydrogen chloride, anhydrous dioxane solution of hydrogen chloride, trifluoroacetic acid or formic acid.

An alternative method for preparing compound (10a) is described below.

[Stage A14]

In this step, compound (18a) is chlorinated to give compound (19a). There are no specific restrictions on the conditions for carrying out such a reaction, and it can be carried out under ordinary chlorination conditions. So, for example, the reaction can be carried out in a solvent, such as phosphorus oxychloride, at a temperature of 0-150 ° C. It is preferable to use a 10-200-fold mass excess of the chlorinating agent.

In the case where R ^p3 is a tert-butoxycarbonyl group which is removed under the above conditions involving the use of phosphorus oxychloride, re-introduction of the protective group is required.

There are no particular restrictions on the conditions for the introduction of the protective group, when R ^p3 is a tert-butoxycarbonyl group, the reaction can be carried out using an -NH-protective agent such as di-tert-butyl dicarbonate in a solvent such as acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran or dimethoxyethane, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, bicarb potassium onate, sodium bicarbonate or triethylamine, at a temperature of 0-150ºС.

[Stage A15]

In this step, compound (19a) is partially hydrolyzed to give compound (20a). The reaction is carried out in the presence of a base such as sodium acetate, potassium carbonate or sodium hydroxide. It is preferable to use 1-10 equivalents of base. Solvents for such a reaction include dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, water, and mixtures thereof. The reaction can be carried out at a temperature of 0-100ºС.

[Stage A16]

At this stage, the compound (20a) and the compound (21a) are reacted to produce the compound (22a). The reaction can be carried out under the same conditions that were used for the [stage A2] production method A.

An alternative method for preparing compound (19a) is described below.

[Stage A17]

At this stage, a substitution reaction is carried out using compound (23a) [CAS No. 1076-22-8] and compound (4a-2) to give compound (24a).

The reaction can be carried out under the same conditions that were used to carry out the [step A4] production method A.

[Stage A18]

In this step, compound (24a) is reacted with a halogenating agent to give compound (25a).

The reaction can be carried out under the same conditions that were used to carry out [stage A5] of the production method A.

[Stage A19]

In this step, compound (25a) is chlorinated to give compound (26a).

There are no particular restrictions on the conditions for carrying out such a reaction, and compound (25a) can react with phosphorus oxychloride, phosphorus pentachloride or a mixture thereof in the presence or absence of a solvent at a temperature of 0-150 ° C. As solvents, toluene, acetonitrile and dichloroethane can be used.

[Stage A20]

In this step, compound (26a) is reacted with compound (7a) to give compound (19a).

The reaction can be carried out under the same conditions that were used to carry out [stage A6] of the production method A.

The method of obtaining In

[Stage B1]

In this step, compound (1b) is benzylated and the sugar chain is cleaved to form compound (2b).

There are no specific restrictions regarding the reaction conditions. Compound (2b) can be prepared by reacting compound (1b) with benzyl bromide in a solvent, such as acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol and ethanol at a temperature 0-150ºС, as a result of adding 3-10 equivalents of hydrochloric acid and incubating the resulting mixture at a temperature of 0-150ºС in order to break down the sugar fragment. It is preferable to use 1-3 equivalents of benzyl bromide.

[Stage B2]

In this step, compound (2b) is reacted with a halogenating agent to give compound (3b). The halogenation reaction can be carried out under the same conditions that were used to carry out [stage A5] in the method of obtaining A.

[Stage B3]

In this step, compound (3b) is reacted with compound (4b) to give compound (5b). The reaction can be carried out under the same conditions as were used for the implementation of [step A6] in the production method A.

[Stage B4]

In this step, compound (5b) is reacted with compound (5b-2) to give compound (6b). The reaction can be carried out under the same conditions as were used for the implementation of [step A2] in the production method A.

[Stage B5]

At this stage, the R ^p3 group of compound (6b) is removed to give compound (7b). The reaction can be carried out under the same conditions as were used for the implementation of [step A13] in the production method A.

The method of obtaining b-2

Compound (9b) of the general formula

can be obtained using the compound represented by the formula H-T ^1a , instead of the compound (7a) in [Step A6] of the production method A described above, under the conditions used for [Step A6], the above chemical reaction sequence is then carried out [Step A7 ] - [stage A13].

Compound (10b) of the general formula

can be obtained using the compound represented by formula H-T ^1a , instead of compound (3b) in [Step B3] of the above production method B, under the conditions used for [Step B3], after which the above chemical reaction sequence [step] B4] - [stage B6]. A preferred example of compound (8b) is piperidin-3-yl-carbamic acid tert-butyl ester.

The method of obtaining C

[Stage C1]

In this step, compound (1c) is reacted with compound (1c-2) to give compound (2c). The reaction can be carried out under the same conditions as used for the implementation of [step A4] in the production method A.

[Stage C2]

In this step, compound (1c) is reacted with ethanol to give compound (3c).

Compound (3c) can be obtained by heating an ethanol solution of compound (2c) under reflux in the presence of an acid such as sulfuric acid. However, reaction conditions are not limited to this example. In the reaction in question, it is preferable to use 1-2 equivalents of acid.

[Stage C3]

In this step, compound (2c) is reacted with ethanol to give compounds (4c) and (5c). The reaction can be carried out under the same conditions as used for the implementation of [step C2] in the process for producing C.

[Stage C4]

In this step, compound (3c) is reacted with compound (3c-2) to give compounds (4c) and (5c). The reaction can be carried out under the same conditions as used for the implementation of [step A4] in the production method A.

[Stage C5]

At this stage, the compound (4c) is reacted with the compound (6c) to give the compound (7c). The reaction can be carried out under the same conditions as were used for the implementation of [step A6] in the production method A.

[Stage C6]

In this step, compound (7c) is thioamidated to give compound (8c). The solvents used in the reaction may be acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran and dimethoxyethane. Reagents used for carrying out the thioamidation reaction include ammonium sulfide, sodium sulfide and hydrogen sulfide. It is preferable to use 2-10 equivalents of a thioamidating reagent. When using hydrogen sulfide as a thioamidating reagent, the reaction is carried out in the presence of a base such as triethylamine or N, N-diisopropylethylamine. The reaction can be carried out at a temperature of 0-150ºС.

[Stage C7]

In this step, compound (8c) is reacted with a methylating reagent to give compound (9c). As methylating reagents, trimethyloxonium tetrafluoroborate, methyl sulfate, methyl iodide, trimethyl phosphite can be used. It is preferable to use 1.0-1.5 equivalents of methylating reagent.

When using trimethyloxonium tetrafluoroborate as a methylating reagent, compound (9c) can be obtained by carrying out the reaction in a halogenated solvent such as dichloromethane at a temperature in the range of 0-50 ° C.

By using methyl sulfate, methyl iodide or trimethyl phosphite as the methylating reagent, compound (9c) can be prepared by reacting in the presence of a base such as potassium carbonate, triethylamine or N, N-diisopropylethylamine. In this case, it is preferable to use 1, -1.5 equivalents of base. Acetone, N, N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran and dimethoxyethane can be used as a solvent in this reaction. The reaction can be carried out at a temperature of 0-100ºС.

[Stage C8]

In this step, compound (9c) is hydrolyzed to give compound (10c).

The conditions for the hydrolysis reaction are not regulated. The reaction can be carried out in a mixed solvent consisting of ethanol and water, in the presence of an acid, such as sulfuric, hydrochloric or p-toluenesulfonic acid, at a temperature of 0-80ºС. In the present case, it is preferable to use 5-50 equivalents of acid.

In the case when the group R ^p3 is a tert-butoxycarbonyl group which is removed under the above reaction conditions, the protective group should be introduced again. The conditions for the reaction of introducing a protective group are not regulated. In the case where the R ^p3 group is a tert-butoxycarbonyl group, the reaction can be carried out using a reagent such as tert-butyl dicarbonate in a solvent such as dichloromethane, chloroform, N, N-dimethylformamide or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine and N, N-diisopropylethylamine, at a temperature of 0-80 ° C. In this case, it is preferable to use 2-3 equivalents of base.

[Stage C9]

In this step, compound (10c) is reacted with a reducing agent to give compound (11c).

The conditions for the reaction of recovery are not regulated. The reaction in question can be carried out by reacting compound (10c) with hydrogen in the presence of Raney nickel in a solvent such as benzene, ethanol, 2-propanol or acetone, at a temperature of 0-50 ° C, or by reacting compound (10c) with a reducing agent, such as sodium borohydride, in a solvent such as methanol, ethanol or 2-methyl-2-propanol, or in a mixed solvent of water and tetrahydrofuran, at a temperature of 0-50 ° C, or the interaction of compound (10c) with a reducing agent, such as borohydride n Tria, in the presence of 1-5 equivalents of a mercuric salt, eg mercuric acetate in a solvent such as methanol, ethanol or 2-methyl-2-propanol, at a temperature 0-50ºS. It is preferable to use 2-3 equivalents of a reducing agent.

[Stage C10]

In this step, compound (11c) is subjected to an oxidation reaction to give compound (12c).

When using oxidizing agents such as manganese dioxide, pyridinium chlorochromate or pyridinium dichromate, compound (12c) can be obtained by carrying out the reaction in a solvent, such as dichloromethane or chloroform, at a temperature in the range of 20-80 ° C. Compound (12c) can also be obtained by carrying out the reaction under ordinary conditions of oxidation of a primary alcohol to an aldehyde, for example, Swern oxidation. It is preferable to use 5-20 equivalents of an oxidizing agent.

[Stage C11]

In this step, compound (12c) is reacted with compound (13c) to give compound (17c). For carrying out such a reaction, it is preferable to use 2-10 equivalents of compound (13c).

Compound (17c) can be prepared by mixing compounds (12c) and (13c) in a solvent such as methanol, ethanol, 1-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran or dimethoxyethane, or in the absence of a solvent, and the subsequent reaction of the mixture at a temperature of 20-150ºC. However, reaction conditions are not limited to this example.

[Stage C12]

In this step, compound (12c) is reacted with hydrazine to give compound (15c). The reaction in question can be carried out under the same conditions as used for [Step C11] of the preparation method C. It is preferable to use 2-10 equivalents of hydrazine.

[Stage C13]

At this stage, a substitution reaction is carried out using compounds (15c) and (16c) to give compound (17c). The reaction in question can be carried out under the same conditions as those used for [Step A2] of the production method A. It is preferable to use 1-3 equivalents of compound (16c).

[Stage C14]

At this stage, the R ^p3 group of compound (17c) is removed and compound (14c) is obtained. The reaction can be carried out under the same conditions as used for [Step A13] of the preparation of A.

[Stage C15]

In this step, compound (5c) is reacted with compound (6c) to give compound (18c). The reaction can be carried out under the same conditions as used for [Step A6] of the preparation of A.

[Stage C16]

In this step, compound (18c) is hydrolyzed to give compound (19c).

The conditions for the hydrolysis reaction are not regulated. So, for example, compound (19c) can be obtained by keeping compound (18c) in the presence of a base at a temperature of 0-100ºС.

As solvents for the reaction in question, methanol, ethanol, tetrahydrofuran, water or mixtures thereof can be used. Used bases include lithium hydroxide, sodium hydroxide and potassium hydroxide. Preferably, 1-2 equivalents of base are used.

[Stage C17]

In this step, compound (19c) is reacted with a reducing agent to give compound (20c). The reaction can be carried out under ordinary conditions of reduction of a carboxylic acid to methyl alcohol.

As reducing agents, borane derivatives such as borane tetrahydrofuran complex and borane methyl sulfide complex, as well as sodium borohydride can be used. It is preferable to use 5-30 equivalents of a reducing reagent.

When using a borane derivative as a reducing agent, compound (20c) can be obtained by carrying out the reaction in a solvent, such as 1,4-dioxane, tetrahydrofuran or dimethoxyethane, at a temperature of from -78 to + 35ºС.

When using sodium borohydride as a reducing agent, the compound (19c) is first reacted with an activator, such as isobutyl chloroformate at a temperature of -78 - + 20ºС, after which it is reacted with a reducing agent, such as sodium borohydride, at a temperature of -78 - + 35ºС, resulting in a compound (20c). As the solvent, 1,4-dioxane, tetrahydrofuran and dimethoxyethane can be used.

[Stage C18]

In this step, compound (20c) is thioamidated to give compound (21c). The reaction can be carried out under the same conditions as used for [Step C6] of the preparation of C.

[Stage C19]

In this step, compound (21c) is reacted with a silylating agent in the presence of a base to form compound (22c).

Solvents used for such a reaction include dichloromethane, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and dimethoxyethane. Bases include imidazole, pyridine, 4-dimethylaminopyridine, triethylamine and N, N-diisopropylethylamine. Silylating agents include tert-butyldimethylchlorosilane and tert-butylchlorodiphenylsilane. Preferably 1.0-1.5 equivalents of base and 1.0-1.5 equivalents of silylating agent are used. The reaction can be carried out at a temperature of 0-80ºС.

[Stage C20]

In this step, compound (22c) is methylated to give compound (23c). The reaction can be carried out under the same conditions as used for [step C7] of the preparation of C.

[Stage C21]

In this step, compound (23c) is hydrolyzed to give compound (24c).

The conditions for the hydrolysis reaction are not regulated. Compound (24c) can be obtained by carrying out the reaction in a mixed solvent consisting of ethanol and water in the presence of an acid such as sulfuric, hydrochloric or p-toluenesulfonic acid, at a temperature of 50-100ºС.

In the event that the group —R ^p3 is removed as a result of the reaction, the group —NH— should be re-protected. So, for example, if -R ^p3 represents a tert-butoxycarbonyl group, then the reaction can be carried out using tert-butyl dicarbonate in a solvent such as dichloromethane, chloroform, N, N-dimethylformamide or tetrahydrofuran, in the presence of a base such as pyridine, aminopyridine , triethylamine or N, N-diisopropylethylamine, at a temperature of 0-80ºC. However, the reaction conditions are not regulated.

The method of obtaining D

[Stage D1]

In this step, compound (1d) is reacted with compound (1d-2) to give compound (2d).

Specific examples of compound (1d-2) include alkyl halides such as iodomethane, iodoethane, iodopropane, benzyl bromide, 2-bromoacetophenone, chloromethylbenzyl ether and bromoacetonitrile; alkenyl halides such as allyl bromide and 1-bromo-3-methyl-2-butene; and alkynyl halides such as propargyl bromide and 1-bromo-2-butine. It is preferable to use 1-1.5 equivalents of compound (1d-2).

The solvents used in the reaction include N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and dichloromethane. The reaction can be carried out in the presence or absence of a base. Useful bases include 1,8-diazabicyclo [5.4.0] undecene, triethylamine, N, N-diisopropylethylamine and sodium hydride. In this case, it is preferable to use 1-1.5 equivalents of base. The reaction can be carried out at a temperature of 0-150ºС.

[Stage D2]

In this step, compound (2d) is reacted with a nitrite salt to give compound (3d).

The solvents for such a reaction may be a mixed solvent of water and substances such as N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane. Nitrites include sodium nitrite and potassium nitrite. It is preferable to use 3-5 equivalents of nitrite. The reaction can be carried out at a temperature of 20-120ºС.

[Stage D3]

In this step, compound (3d) is reacted with ammonia to give compound (4d). It is preferable to use 10-20 equivalents of ammonia.

The reaction can be carried out in a solvent, such as methanol, ethanol or 1,4-dioxane, at a temperature in the range of 20-200 ° C.

[Stage D4]

At this stage, compound (4d) is subjected to catalytic reduction in a hydrogen atmosphere or in the presence of 2-3 equivalents of hydrazine using a metal catalyst and the result is compound (5d).

Solvents used in this reaction include methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, water, or mixtures thereof. Metal catalysts include palladium on carbon, platinum oxide and Raney nickel. The preferred amount of catalyst is 0.5-10 wt.%. The reaction can be carried out at a temperature of 0-150ºС.

[Stage D5]

In this step, compound (5d) is reacted with orthoformate to give compound (6d).

The reaction is carried out in the presence of a carboxylic acid anhydride, for example acetic anhydride. Esters of orthoformic acid include methyl orthoformate and ethyl orthoformate. It is preferable to use a 1-20-fold excess of orthoformate and 3-10 equivalents of carboxylic anhydride. The reaction can be carried out at a temperature of 20-200ºС.

[Stage D6]

In this step, the NH group at position 1 of compound (6d) is protected to give compound (7d).

Protective reagents are N, N-dimethyl sulfamoyl chloride, trityl chloride, di-tert-butyl dicarbonate and benzyl bromide. A preferred amount of protective agent is 1-1.5 equivalents. Solvents in this reaction include dichloromethane, chloroform, carbon tetrachloride, toluene, N, N-dimethylformamide and tetrahydrofuran. Bases used include 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undecene, triethylamine and N, N-diisopropylethylamine. In normal cases, 1.2 equivalents of base are preferred. However, when the protective agent is di-tert-butyl dicarbonate, it is preferred to use 0.005-0.1 equivalents of 4-dimethylaminopyridine. The reaction is carried out at a temperature of 20-200 ° C.

[Stage D7]

In this step, compound (7d) is chlorinated to give compound (8d).

The conditions of this reaction are not regulated. So, for example, the reaction in question can be carried out as follows. At a temperature in the range of -100 - + 20ºС, the compound (7d) is reacted with a base, after which they are reacted with a chlorinating agent. The result is a compound (8d). Compound (8d) can also be obtained by reacting compound (7d) with a base in the presence of a chlorinating agent. Solvents for such a reaction include diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane. Bases used include n-butyllithium, tert-butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and magnesium diisopropylamide. It is preferable to use 1-1.5 equivalents of base. Chlorinating agents include hexachloroethane and N-chlorosuccinimide. A preferred amount of a chlorinating agent is 1-3 equivalents.

[Stage D8]

In this step, compound (8d) is reacted with compound (9d) to give compound (10d). The reaction can be carried out under the same conditions as used for [Step A6] of the preparation of A.

[Stage D9]

At this stage, a substitution reaction was carried out using compounds (10d) and (10d-2) to give compound (11d). The reaction can be carried out under the same conditions as used for [Step A4] of the preparation of A.

[Stage D10]

At this stage, R ^p3 is removed from compound (11d) to give compound (12d). The reaction can be carried out under the same conditions as used for [Step A13] of the preparation of A.

[Stage D11]

At this stage, the group at position 5 of compound (11d) is dealkylated to give compound (13d). The conditions of the dealkylation reaction are not specifically regulated. So, for example, the reaction can be carried out as follows.

In the case where R ¹ represents a benzyloxymethyl group, the compound (11d) is reacted with 3-10 equivalents of boron tribromide, boron trichloride, and the like. in a solvent such as dichloromethane, at a temperature in the range of -100 - + 20 ° C. The result is a compound (13d).

If, when carrying out such a reaction, the group R ^p3 is removed, then the group -NH- should be re-protected. So, for example, if R ^p3 represents a tert-butoxycarbonyl group, then the reaction in question can be carried out using a reagent such as di-tert-butyl dicarbonate in a solvent such as dichloromethane, chloroform, N, N-dimethylformamide or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine or N, N-diisopropylethylamine, at a temperature of 0-80 ° C. However, the reaction in question can be carried out under other conditions.

[Stage D12]

In this step, compound (13d) is reacted with compound (13d-2) to give compound (14d). The reaction can be carried out under the same conditions as used for [Step D1] of the preparation of D.

[Stage D13]

At this stage, R ^p3 is removed from compound (14d) to give compound (12d). The reaction can be carried out under the same conditions as used for [Step A13] of the preparation of A.

An alternative method for preparing compound (11d) is described below.

[Stage D14]

At this stage, a protecting group is removed from compound (8d) to give compound (15d).

The deprotection reaction can be carried out under normal conditions, depending on the nature of the protecting group. So, for example, in the case of a tert-butoxycarbonyl group, the deprotection can be carried out using a base such as sodium hydroxide, potassium carbonate and ammonia in tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol, water or mixtures thereof at temperature 0-100ºС. In the case where the solvent and base are added after chlorination in the previous step, deprotection can be carried out without isolating compound (8d).

[Stage D15]

In this step, X is introduced into compound (15d) to give compound (16d). The reaction can be carried out using XU ² under the same conditions as used in [Step A4] of the preparation of A.

Alcohol (X-OH) may be administered using the Mitsunobu reaction. Compound (16d) can be prepared by reacting an alcohol (X-OH) with dialkyl ether of azodicarboxylic acid and triphenylphosphine in a solvent such as tetrahydrofuran at a temperature of -70 - 50 ° C.

[Stage D16]

In this step, compound (16d) is reacted with compound (9d) to give compound (11d). The reaction can be carried out under the same conditions as used for [Step A6] of the preparation of A.

The method of obtaining E

Compound (1e) represented by the formula

can be obtained using compound (8b) of the formula H-T ^1a instead of compound (6c) in [step C5] or [step C15] of the above production method C under the same conditions as those used in [step C5], followed by reactions in the above sequence [stage C6] - [stage C21].

Compound (1e) represented by the formula

can be obtained using compound (8b) of the formula H-T ^1a instead of compound (9d) in [step D8] of the above production method D under the same conditions as used in [step D8], followed by the reactions in the above sequence [stage C9] - [stage C13].

The method of obtaining F

[Stage F1]

At this stage, the ester group of compound [1f] is hydrolyzed to give compound (2f). Such a reaction can be carried out under the same conditions that were used during the [stage C16] method for producing C.

[Stage F2]

At this stage, R ^p3 is removed from compound (2f) to form compound (3f). The reaction in question can be carried out under the same conditions as used for the implementation of [step A13] of the production method A.

The method of obtaining G

[Stage G1]

At this stage, nitro groups are reduced in the molecule of compound (1g) to give compound (2g).

In this reaction, methanol, ethanol, tetrahydrofuran, water or mixtures thereof can be used as solvents. As reducing agents, iron, tin and zinc can be used. Hydrochloric acid and ammonium salts such as ammonium chloride can serve as catalysts. The reaction can be carried out at a temperature of 20-120ºС.

[Stage G2]

At this stage, R ^p3 is removed from compound (2g) to give compound (3g). The reaction can be carried out under the same conditions as used for [Step A13] of the preparation of A.

The method of obtaining N

[Stage H1]

At this stage, the nitrile group of compound (1h) is hydrolyzed to give compound (2h).

The conditions for such a reaction are not specifically regulated. So, for example, the reaction can be carried out as follows. Compound (2h) can be obtained by reacting compound (1h) with hydrogen peroxide in the presence of a base at a temperature of -20 - + 50ºС. As solvents, methanol, ethanol, tetrahydrofuran, water or mixtures thereof can be used. Bases include ammonia and an alkylamine such as triethylamine.

[Stage H2]

At this stage, R ^p3 is removed from compound (2h) to give compound (3h). The reaction can be carried out under the same conditions as used for [Step A13] of the preparation of A.

The method of obtaining I

[Stage I1]

In this step, compound (1i) is reacted with an alkyl metal or aryl metal reagent to give compound (2i).

The conditions for such a reaction are not specifically regulated. So, for example, the reaction can be carried out as follows. Compound (1i) can be reacted with a reagent, such as alkyl lithium, aryllithium, an alkyl Grinyarovsky reagent, or an aryl Grinyarovsky reagent in a solvent, such as diethyl ether or tetrahydrofuran, at a temperature in the range from -100 to + 100ºС. According to another method, said compound can be reacted with alkylzinc or arylzinc in a solvent such as N, N-dimethylformamide or 1-methyl-2-pyrrolidone at a temperature of 0-50 ° C.

[Stage I2]

In this step, compound (2i) is oxidized to give compound (3i). As an oxidizing agent, a typical reagent can be used, which is used for the oxidation of alcohols. So, for example, manganese dioxide in a solvent, such as dichloromethane or chloroform, at a temperature of 20-100ºС can be used as an oxidizing agent. According to another method, pyridine sulfotrioxide in a solvent such as dimethyl sulfoxide can be used as an oxidizing agent at a temperature in the range of 20-100 ° C. A Dess-Martin periodinan may also be used in a solvent such as chloroform at a temperature of -50 to + 50 ° C.

[Stage I3]

In this step, compound (3i) is reacted with hydrazine to give compound (4i). The reaction can be carried out under the same conditions that are used to carry out [step C12] of the method for producing C.

[Stage I4]

At this stage, substitution is carried out using compounds (4i) and (5i) to give compound (6i). The reaction can be carried out under the same conditions as that used for [Step A2] of the preparation of A.

[Stage I5]

At this stage, the R ^p3 group is removed from the molecule of compound (6i) to give compound (7i). The reaction can be carried out under the same conditions as used for [Step A13] of the preparation of A.

[Stage I6]

At this stage, the group R ^p3 is removed from the molecule of compound (4i) to obtain compound (7i), in the case when R ¹ in compound (7i) is H. The reaction in question can be carried out under the same conditions as used for [ stage A13] method of obtaining A.

The method of obtaining J

[Stage J1]

In this step, compound (1j) is reacted with a cyanidating reagent in the presence of a catalyst to give compound (2j).

Sodium cyanide and potassium cyanide are used as cyanidizing agents. The catalyst is acetic acid. An example of a solvent is acetonitrile. The reaction can be carried out at a temperature of 0-100ºС.

[Stage J2]

At this stage, the nitrile group of compound (2j) is hydrolyzed to give compound (3j). The reaction in question can be carried out under the same conditions as used for the [Step H1] process for producing N.

[Stage J3]

In this step, the hydroxyl group of compound (3j) is oxidized to give compound (4j). The reaction in question can be carried out under the same conditions as used for [stage I2] of the production method I.

[Stage J4]

In this step, compound (4j) is reacted with compound (5j) to give compound (6j). The reaction in question can be carried out under the same conditions as [step C11] of the process for producing C.

[Stage J5]

At this stage, the R ^p3 group is removed from compound (6j) to give compound (7j). The reaction in question can be carried out under the same conditions as [stage A13] of the preparation of A.

[Stage J6]

At this stage, the carbamoyl group of compound (6j) is dehydrated in the presence of a base to give compound (8j).

Dehydrating agents include, for example, phosphorus oxychloride. Bases may include alkylamines such as triethylamine. Dichloromethane and chloroform may be used as solvents. The reaction can also be carried out in the absence of a solvent. The reaction is carried out at a temperature of 0-100ºС.

[Stage J7]

At this stage, the R ^p3 group is removed from compound (8j) to give compound (9j). The reaction can be carried out under the same conditions as [stage A13] of the preparation of A.

The method of obtaining K

[Stage K1]

At this stage, substitution is carried out with the participation of compounds (1k) and (2k) to form compound (3k). The reaction can be carried out under the same conditions as [stage A2] of the production method A.

[Stage K2]

At this stage, substitution is carried out with the participation of compounds (3k) and (4k) to form compound (5k).

Compound (5k) can be obtained, for example, by reacting a mixture of compounds (3k) and (4k) in a solvent such as methanol, ethanol, 1-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran or dimethoxyethane, or lack of solvent at a temperature of 20-200ºС. However, reaction conditions are not limited to this example.

[Stage K3]

In this step, compound (5k) is chlorinated to give compound (6k). The reaction can be carried out under the same conditions as [step D7] of the preparation of D.

[Stage K4]

In this step, compound (6k) is reacted with compound (7k) to give compound (8k). The reaction can be carried out under the same conditions as [stage A6] of the production method A.

[Stage K5]

At this stage, the R ^p5 group of compound (8k) is removed to give compound (9k).

The deprotection reaction of R ^p3 can be carried out under normal conditions of removal of the -NH-protecting group.

In the case when R ^p5 represents a benzyl group, the reaction can be carried out in the presence of a metal such as lithium or sodium in liquid ammonia at temperatures from -78 to -30 ° C.

[Stage K6]

At this stage, substitution is carried out with the participation of compounds (9k) and (10k) to form compound (11k). The reaction can be carried out under the same conditions as [stage A4] of the production method A.

[Stage K7]

At this stage, the R ^p3 group of compound (11k) is removed to obtain compound (12k). The reaction can be carried out under the same conditions as [stage A13] of the preparation of A.

The method of obtaining L

[Stage L1]

In this step, compound (1l) is reacted with compound (2l) in the presence of an oxidizing agent to give compound (3l).

Oxidizing agents include salts such as ferric chloride (III). Solvents include methanol, ethanol and water. The reaction can be carried out at a temperature of 20-100ºС.

If, as a result of the reaction, the -R ^p3 group is removed, then the -NH- group must be re-protected. So, for example, if R ^p3 is a tert-butoxycarbonyl group, then the reaction is carried out in the presence of a reagent such as di-tert-butyl dicarbonate in a solvent such as dichloromethane, chloroform, N, N-dimethylformamide or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine or N, N-diisopropylethylamine, at a temperature of 0-80 ° C. However, the reaction is not limited to the above example.

[Stage L2]

In this step, compound (3l) is reacted with compound (4l) to give compound (5l). The reaction can be carried out under the same conditions as [stage A4] of the production method A.

[Stage L3]

At this stage, the R ^p3 group of compound (5l) is removed to give compound (6l). The reaction can be carried out under the same conditions as [stage A13] of the preparation of A.

The method of obtaining M

[Stage M1]

In this step, compound (1m) is reacted with compound (2m) to give compound (3m). The reaction can be carried out under the same conditions as [stage A6] of the production method A.

[Stage M2]

In this step, compound (3m) is reacted with compound (4m) to give compound (5m). The reaction can be carried out under the same conditions as [stage A4] of the production method A.

[Stage M3]

At this stage, the R ^p3 group of compound (5m) is removed to obtain compound (6m). The reaction can be carried out under the same conditions as [stage A13] of the preparation of A.

The method of obtaining N

[Stage N1]

In this step, compound (1n) is reacted with allylamine to give compound (2n).

The reaction can be carried out at a temperature of 20-150ºС. Solvents for the reaction in question include methanol, ethanol, water, and mixtures thereof.

[Stage N2]

At this stage, the chlorinated compound (2n) is reduced to form compound (3n).

Salts such as tin chloride can be used as a reducing agent. Solvents include concentrated hydrochloric acid. The reaction can be carried out at a temperature of 20-150ºС.

[Stage N3]

In this step, compounds (3n) are reacted with N, N'-disuccinimidyl carbonate to give compound (4n).

This reaction can be carried out in a solvent such as acetonitrile or tetrahydrofuran. The reaction can be carried out at a temperature of 20-100ºС.

[Stage N4]

In this step, the compound (4n) and the compound (5n) are reacted to produce the compound (6n). The reaction can be carried out under the same conditions as [stage A4] of the production method A.

[Stage N5]

At this stage, the allyl group is removed from compound (6n) to give compound (7n).

Compound (7n) can be obtained, for example, by reacting compound (6n) with osmic acid and sodium periodate in a solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or water, at a temperature of 20-100 ° C. However, reaction conditions are not limited to this example.

[Stage N6]

In this step, compound (7n) is chlorinated to give compound (8n).

The conditions for such a reaction are not specifically regulated. The reaction can be carried out under ordinary chlorination conditions. For example, compound (8n) can be prepared using a reagent such as phosphorus pentachloride in a solvent such as phosphorus oxychloride at a temperature of 0-150 ° C.

[Stage N7]

In this step, compound (8n) is reacted with compound (9n) to give compound (10n). The reaction can be carried out under the same conditions as [stage A6] of the production method A.

[Stage N8]

At this stage, the R ^p3 group of compound (10n) is removed to give compound (11n). The reaction can be carried out under the same conditions as [stage A13] of the preparation of A.

The method of obtaining About

[Stage O1]

At this stage, the hydroxyl group of compound (1o) is oxidized to give compound (2o). The reaction can be carried out under the same conditions as [stage I2] of the production method I.

[Stage O2]

In this step, compound (2o) is reacted with ethyl diethylphosphonoacetate in the presence of a base to give compound (3o).

Bases include sodium hydride and lithium diisopropylamide. Solvents include, for example, tetrahydrofuran and N, N-dimethylformamide. The reaction can be carried out at a temperature of 0-100ºС.

[Stage O3]

In this step, the ester derivative of compound (3 °) is hydrolyzed to give compound (4 °). The reaction can be carried out under the same conditions as [stage C16] of the process for producing C.

[Stage O4]

In this step, compound (4 °) is reacted with diphenylphosphoryl azide in the presence of a base to give compound (5 °).

Solvents for the reaction in question include toluene, tert-butanol, tetrahydrofuran and dichloromethane. Bases include tertiary amines such as triethylamine and diisopropylethylamine. The reaction can be carried out at a temperature of -50 - + 50ºС.

[Stage O5]

In this step, compound (5 °) is rearranged to give compound (6 °).

Such a reaction can be carried out in tert-butanol at a temperature of 50-100ºС.

[Stage O6]

At this stage, the nitrile group of compound (6 °) is hydrolyzed to give compound (7 °). The reaction can be carried out under the same conditions as [stage H1] of the process for producing N.

[Stage O7]

In this step, compound (7 °) is reacted with an acid to give compound (8 °).

Acids include sulfuric acid, sulfuric acid and trifluoroacetic acid. Solvents include methanol, ethanol, 1,4-dioxane, water, and mixtures thereof. The temperature at which the interaction is carried out is in the range of 0-50 ° C.

The method of obtaining P

[Stage P1]

At this stage, compounds (1p) are protected to form compound (2p).

As a reagent for protecting the —NH group, a conventional reagent used to protect the NH groups can be used. So, for example, when R ^p3 is a tert-butoxycarbonyl group, the reaction can be carried out at a temperature of 0-80 ° C using a reagent such as tert-butyl dicarbonate in a solvent such as dichloromethane, chloroform, N, N-dimethylformamide and tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine and N, N-diisopropylethylamine.

[Stage P2]

In this step, compound (2p) is reacted with compound (3p) to give compound (4p). The reaction can be carried out under the same conditions as [stage A2] of the production method A.

[Stage P3]

At this stage, the R ^p3 group of the compound (4p) is removed to obtain the compound (5p). The reaction can be carried out under the same conditions as [stage A13] of the preparation of A.

The method of obtaining Q

[Stage Q1]

In this step, compound (1q) is hydrolyzed to give compound (2q).

Solvents for this reaction include tetrahydrofuran, methanol and ethanol. Acids include inorganic acids such as hydrochloric and sulfuric acid. The reaction can be carried out at a temperature of 0-100ºС.

[Stage Q2]

At this stage, the hydroxyl group of compound (2q) is subjected to an oxidation reaction to form compound (3q). The reaction can be carried out under the same conditions as those used for [Step I2] of the production method I.

[Stage Q3]

In this step, compounds (3q) are reacted with methylbenzyloxycarbonylamino (dimethoxyphosphoryl) acetate in the presence of a base to give compound (4q).

Bases include sodium hydride, potassium tert-butylate and 8-diazabicyclo [5.4.0] -7-undecene. Solvents include dichloromethane, tetrahydrofuran and N, N-dimethylformamide. The reaction can be carried out at a temperature of 0-100ºС.

[Stage Q4]

In this step, compounds (4q) are reacted with sodium methylate to give compound (5q).

As a solvent, methanol can be used. The reaction can be carried out at a temperature of 0-80ºС.

[Stage Q5]

In this step, compound (5q) is reacted with compound (6q) to give compound (7q). The reaction can be carried out under the same conditions as those used for [Step A2] of the preparation of A.

[Stage Q6]

In this step, compound (7q) is reacted with an acid to give compound (8q). The reaction can be carried out under the same conditions as those used for [Step O7] of the preparation of O.

[Stage Q7]

At this stage, the R ^p3 group of compound (8q) is removed to give compound (9q). The reaction can be carried out under the same conditions as [stage A13] of the preparation of A.

[Stage Q8]

In this step, compound (7q) is reacted with ammonia to give compound (10q).

Solvents for the reaction include methanol, ethanol and water. The reaction can be carried out at a temperature of 20-150ºС.

[Stage Q9]

At this stage, the R ^p3 group of compound (10q) is removed to obtain compound (11q). The reaction can be carried out under the same conditions as [stage A13] of the preparation of A.

The following compounds, their salts or hydrates thereof, are extremely useful as intermediates in the synthesis of compound (I) of the present invention.

Compounds or their salts or hydrates represented by the general formula

[where R ¹ has the meanings indicated in paragraph [1] above;

R ^p5 represents a tert-butoxycarbonyloxy group, a trityl group or a group represented by the formula —SO ₂ NH ₂ ;

T ¹⁰ represents a halogen atom];

Compounds, their salts or hydrates of the general formula

[where R ¹ has the meanings indicated in paragraph [1] above;

T ¹¹ represents a halogen atom or a group of the general formula

T ¹³ represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a formyl group];

Compounds, their salts or hydrates of the general formula

[where R ¹ has the meanings indicated in paragraph [1] above;

T ¹² represents a halogen atom];

Compounds, their salts or hydrates of the general formula

[where X has the meanings specified in paragraph [1], except when X is a benzyl group;

T ²¹ and T ²² each independently represent a halogen atom;

T ¹¹ represents a halogen atom or a group represented by the general formula

T ¹³ represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a formyl group];

Compounds, their salts or hydrates represented by the general formula

[where X and R ¹ have the meanings indicated in paragraph [1] above;

T ²² represents a halogen atom;

T ¹³ represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a formyl group].

The above methods are representative methods for the preparation of compound (I) of the present invention. The starting compounds and various reagents used in the methods for preparing the compounds of the present invention can be salts, hydrates or solvates depending on the nature of the starting compounds, such as solvents and the like, and there are no special restrictions on these substances if they are not inhibit the described reactions. The type of solvent used depends on the nature of the starting compounds, the reagents used, etc. and it is not specifically regulated if such substances do not inhibit the reaction and sufficiently dissolve the starting materials. In the case when the compound (I) of the present invention is obtained in free form, this compound can be converted in the usual way into its salt or hydrate, which is a possible form of the above compound (I).

In the case where the compound (I) of the present invention is obtained in the form of a salt or hydrate, such a product can be converted into the free form of the above compound (I) in the usual way.

In addition, various isomers of compound (I) of the present invention (for example, geometric isomers, enantiomers whose formation is due to the presence of an asymmetric carbon atom, rotamers (rotational isomers), stereoisomers and tautomers) can be isolated and purified by conventional methods, such as recrystallization , the formation of diastereomeric salts, enzymatic separation and various chromatographic methods (for example, thin layer chromatography, column chromatography and gas chromatography).

The compounds of the present invention, their salts or hydrates can be conventionally incorporated into tablets, powders, particles, granules, coated tablets, capsules, syrups, pills, inhalers, suppositories, injectable preparations, ointments, eye lapping, eye drops, drops for nose, ear drops, poultices, lotions, etc. Such formulations can be formulated using conventional diluents, binders, lubricants, colorants, flavors, and, if desired, stabilizers, emulsifiers, absorption enhancers, surfactants, pH modulators, preservatives, antioxidants, etc., and also materials that are commonly used as ingredients in pharmaceutical formulations. For example, an oral preparation can be prepared by mixing a compound of the present invention or a pharmaceutically acceptable salt thereof with a diluent and, if necessary, with a binder, disintegrant, lubricating agent, coloring agent, flavoring agent and the like. and conventionally forming the resulting mixture in the form of powders, particles, granules, tablets, coated tablets, capsules, and the like. Examples of such materials include animal and vegetable fats, such as soybean oil, beef tallow, and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and paraffin wax; essential oils, for example octyldodecyl myristate and isopropyl myristate; higher alcohols, for example cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid ester, sorbitol fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene hydrogenated castor oil and polyoxyethylene polyoxypropylene block copolymer; water soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powder, such as anhydrous silicic acid, magnesium aluminum silicate and aluminum silicate, as well as purified water. Examples of diluents include lactose, wheat starch, sugar, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide. As binders, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block copolymene can be used. Examples of disintegrants are starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and calcium carboxymethyl cellulose. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica and hydrogenated vegetable oil. As dyes, pharmaceutically applicable substances can be used. Examples of flavoring agents include cocoa powder, mint camphor, flavored peppermint oil powder, Borneo camphor and cinnamon powder. Tablets and granules may be sugar coated or, if necessary, another suitable coating may be applied. Solutions, for example syrups or injectable preparations, can be prepared by mixing the compounds of the present invention or their pharmaceutically acceptable salts with a pH modulator, solubilizing agent, isotonic agent, and the like. and, if necessary, with an auxiliary solvent, stabilizer, etc. There are no particular restrictions regarding the methods of preparing preparations for external use, and such preparations can be prepared by conventional methods. A variety of materials commonly used for the manufacture of pharmaceuticals, quasi-drugs, cosmetics, and the like can be used as the basis for topical preparations. Examples of such basic materials are animal and vegetable oils, mineral oils, essential oils, waxes, higher alcohols, fatty acids, silicone oil, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clays and purified water. In addition, the preparations of the present invention for external use, if necessary, may contain pH modulators, antioxidants, chelating agents, antibacterial / antifungal agents, colorants, deodorants, and the like. However, the topical preparations of the present invention are not limited to the basic materials of these types. If necessary, such preparations may contain differentiation stimulants, blood supply improving agents, antimicrobial agents, anti-inflammatory agents, cell activators, vitamins, amino acids, moisturizers, keratolytic agents, and the like. The amount of the above basic materials is regulated so that it falls into the concentration range used to obtain conventional external preparations.

Upon administration of a compound of the present invention, its salt or hydrate, the forms of the compound are not regulated and the compound may be administered in the usual oral or parenteral manner. So, for example, the compound can be administered in unit dosage form, such as tablets, powders, granules, capsules, syrups, pills, inhalers, suppositories, injectables, ointments, eye ointments, eye drops, nose drops, ear drops, compresses and lotions. The dose of the pharmaceutical preparation of the present invention may be selected depending on the severity of the symptoms, age, gender and weight of the patient, form of the compound, type of salt, nature of the disease, and the like.

Dosage may vary depending on the type of disease, the severity of the symptoms, age and gender of the patient, drug tolerance, etc. The pharmaceutical agent of the present invention is used one or more times with a dose of 0.03 to 1000 mg / adult patient / day, preferably 0.10-500 mg / adult patient / day, more preferably 0.1-100 mg / adult patient / day. The injection dose may be 1-3000 μg / kg, preferably 3-1000 μg / kg.

Compounds of the present invention can be obtained, for example, by the methods described in the following examples. However, the compounds of the present invention are in no way limited to the specific examples described below.

[Production Examples]

Production Example 1

tert-Butyl-4- [1- (2-butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate

(a) tert-Butyl-5-methyl-4-oxo-4,5-dihydroimidazo [4,5-d] pyridazine-1-carboxylate

A mixture consisting of 1.0 g of 5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one, 16 mg of 4-dimethylaminopyridine, 1.6 g of di-tert-butyl dicarbonate and 5 ml of tetrahydrofuran, stirred at room temperature overnight. Then, 0.5 ml of a tetrahydrofuran solution containing 300 mg of di-tert-butyl dicarbonate was added to the solution, and the resulting mixture was stirred at room temperature for three hours. 5 ml of tert-butyl methyl ether was added to the reaction mixture, and the mixture was cooled with ice. The resulting crystals were collected by filtration to obtain 1.63 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.72 (s, 9H), 3.39 (s, 3H), 8.38 (s, 1H), 8.54 (s, 1H).

b) 2-Chloro-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one

8.4 ml of lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution) is added dropwise over one hour to 300 ml of a tetrahydrofuran solution containing 1.68 g of tert-butyl-5-methyl-4-oxo-4,5-dihydroimidazo [ 4,5-d] pyridazine-1-carboxylic acid and 4.15 g of hexachloroethane in a nitrogen atmosphere at 0 ° C. The resulting mixture was stirred for 30 minutes. To the solution add 2 N. aqueous ammonia solution and the mixture is stirred for three hours. Then the reaction solution was concentrated to 50 ml and washed with 20 ml of tert-butyl methyl ether. The solution was acidified with concentrated hydrochloric acid. The precipitate formed is collected by filtration and washed successively with 10 ml of water and 10 ml of tert-butyl methyl ether. Thus, 1.03 g of the title compound is obtained.

¹ H-NMR (DMSO-d ₆ )

δ 1.45 (s, 9H) 3.72 (s, 3H), 8.33 (s, 1H).

(c) 3- (2-Butynyl) -2-chloro-5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one

7.72 g of 2-chloro-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one is suspended in 400 ml of tetrahydrofuran in a nitrogen atmosphere and 14.22 g of triphenylphosphine and 3.85 g of 2 are added -butin-1-ol. The resulting mixture is cooled to 0 ° C. 100 ml of a tetrahydrofuran solution containing 12.55 g of azodicarboxylic acid di-tert-butyl ester are added dropwise and the reaction mixture is stirred for three hours. The resulting mixture was concentrated under reduced pressure. 50 ml of dichloromethane and 50 ml of trifluoroacetic acid were added to the residue, and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting precipitate was dissolved in 400 ml of ethyl acetate and washed with 200 ml of 5 N. an aqueous solution of sodium hydroxide. The aqueous layer was extracted with 100 ml of ethyl acetate. The organic layers are combined, dried over magnesium sulfate and concentrated under reduced pressure. The resulting precipitate was purified by silica gel column chromatography. Thus, from the fraction eluted with hexane-ethyl acetate (4: 1), 8.78 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ )

δ 1.82 (t, J = 2.3 Hz, 3H), 3.87 (s, 3H), 5.32 (q, J = 2.3 Hz, 2H), 8.19 (s, 1H) .

(d) tert-Butyl-4- [1- (2-butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin- 1-carboxylate

5 ml of 1-methyl-2-pyrrolidone in a nitrogen atmosphere is added to a mixture consisting of 1.183 g of 3- (2-butynyl) -2-chloro-5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin- 4-one, 0.829 g of potassium carbonate and 1.395 g of tert-butylpiperazine-1-carboxylate. The resulting mixture is heated at 130 ° C for 6 hours. The reaction mixture was cooled and 50 ml of water was added. The mixture is then extracted with 100 ml of ethyl acetate. The organic layer was washed twice with 50 ml of water and then with 50 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting precipitate was purified by silica gel column chromatography. Thus, 1.916 g of the title compound is obtained from the fraction eluted with hexane-ethyl acetate (1: 4).

¹ H-NMR (CDCl ₃ )

δ 1.52 (s, 9H), 1.83 (t, J = 2.3 Hz, 3H), 3.38-3.42 (m, 4H), 3.61-3.64 (m, 4H) ), 3.85 (s, 3H), 5.09 (q, J = 2.3 Hz, 2H), 8.13 (s, 1H).

Production Example 2

tert-Butyl-4- [7- (2-butynyl-2,6-dichloro-7H-purin-8-yl] piperazine-1-carboxylate

(a) 7- (2-Butynyl) -3-methyl-3,7-dihydropurin-2,6-dione

55.3 ml of 1-bromo-2-butine and 84.9 g of anhydrous potassium carbonate are added to a mixture of 100 g of 3-methylxanthine [CAS No. 1076-22-8] and 1000 ml of N, N-dimethylformamide. The resulting mixture was stirred at room temperature for 18 hours. 1000 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The resulting white precipitate was filtered off. The white solid was washed with water and then with tert-butyl methyl ether. Thus, 112 g of the title compound are obtained.

¹ H-NMR (DMSO-d ₆ )

δ 1.82 (t, J = 2.2 Hz, 3H), 3.34 (s, 3H), 5.06 (q, J = 2.2 Hz, 2H), 8.12 (s, 1H) 11.16 (br s, 1H).

(b) 7- (2-Butynyl) -8-chloro-3-methyl-3,7-dihydropurin-2,6-dione

112 g of 7- (2-butynyl) -3-methyl-3,7-dihydropurin-2,6-dione are dissolved in 2200 ml of N, N-dimethylformamide and 75.3 g of N-chlorosuccinimide are added. The resulting mixture was stirred at room temperature for five hours. 2200 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. The resulting white precipitate was collected by filtration and washed successively with water and tert-butyl methyl ether. Thus, 117 g of the title compound is obtained.

¹ H-NMR (DMSO-d ₆ )

δ 1.78 (t, J = 2.0 Hz, 3H), 3.30 (s, 3H), 5.06 (q, J = 2.0 Hz, 2H), 11.34 (br s, 1H).

(c) 7- (2-Butynyl) -2,6,8-trichloro-7H-purine

A mixture consisting of 2.52 g of 7- (2-butynyl) -8-chloro-3-methyl-3,7-dihydropurin-2,6-dione and 100 ml of phosphorus oxychloride was stirred at 120 ° C for 14 hours. After the reaction mixture was cooled, 4.15 g of phosphorus pentachloride was added to the solution. The resulting mixture was stirred at 120 ° C for 24 hours. After the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran. The resulting solution was poured into a saturated sodium bicarbonate solution and the resulting mixture was extracted with ethyl acetate. The resulting organic layer was washed with water, then with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, 1: 3) to obtain 2.40 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.82 (t, J = 2.4 Hz, 3H), 5.21 (q, J = 2.4 Hz, 2H).

(d) tert-Butyl-4- [7- (2-butynyl-2,6-dichloro-7H-purin-8-yl] piperazine-1-carboxylate

A mixture of 2.4 g of 7- (2-butynyl) -2,6,8-trichloro-7H-purine, 1.46 g of sodium bicarbonate, 2.43 g of tert-butylpiperazine-1-carboxylate and 45 ml of acetonitrile are stirred at room temperature for 2 hours 20 minutes. Then 0.73 g of sodium bicarbonate and 1.21 g of tert-butyl piperazine-1-carboxylate are added and the resulting mixture is stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate-water, and the organic layer was washed with 1N. hydrochloric acid, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is taken up in diethyl ether. The resulting crystals were collected by filtration and washed with diethyl ether. Thus, 3.0 g of the title compound is obtained as a white solid.

¹ H-NMR (DMSO-d ₆ )

δ 1.42 (s, 9H), 1.83 (t, J = 2 Hz, 3H), 3.48-3.55 (m, 4H), 3.57-3.63 (m, 4H), 4.89 (q, J = 2 Hz, 2H).

[Examples]

Example 1

Ethyl [7- (2-chlorophenyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] acetate trifluoroacetate

(a) [7-Benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl 2,2-dimethylpropionate

8.66 g of 7-benzylxanthine was dissolved in 300 ml of N, N-dimethylformamide and 1.57 g of sodium hydride and 7.7 ml of chloromethyl pivalate were added. The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with water and 1 N. hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.66 g of the title compound are obtained from the fraction eluted with hexane-ethyl acetate (1: 1).

¹ H-NMR (CDCl ₃ )

δ 1.18 (s, 9H), 5.45 (s, 2H), 6.06 (s, 2H), 7.34-7.39 (m, 5H), 7.58 (s, 1H), 8.18 (s, 1H).

(b) [7-Benzyl-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl 2,2-dimethylpropionate

2.66 g of [7-benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl 2,2-dimethylpropionate are dissolved in 30 ml of N, N-dimethylformamide and 1.6 g are added potassium carbonate and 1 ml of methyl iodide. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and 1 N. hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue is treated with toluene. Thus, 2.16 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ )

δ 1.18 (s, 9H), 3.41 (s, 3H), 5.49 (s, 2H), 6.11 (s, 2H), 7.26-7.39 (m, 5H), 7.57 (s, 1H).

(c) [1-Methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl-2,2-dimethylpropionate

2.349 g of [7-benzyl-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl 2,2-dimethylpropionate is dissolved in 100 ml of acetic acid and 1 g of catalyst is added to the solution , representing 10% palladium on charcoal. The resulting mixture was stirred in a hydrogen atmosphere at room temperature overnight. The mixture was filtered and concentrated to give 1.871 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.19 (s, 9H), 3.48 (s, 3H), 6.17 (s, 2H), 7.83 (s, 1H).

(d) [7- (2-Chlorophenyl) -1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl 2,2-dimethylpropionate

1.60 g of [1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl 2,2-dimethylpropionate, 1.83 g of 2-chlorophenylboronic acid and 1.5 g of acetate copper (II) is suspended in 30 ml of N, N-dimethylformamide and 3 ml of pyridine is added to the resulting suspension. The resulting mixture was stirred at room temperature for 3 days. The reaction solution was filtered through a short column filled with silica gel, and the filtrate was diluted with ethyl acetate. The organic layer is washed with 1 N. hydrochloric acid, water and saturated brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated. The residue was suspended in ether and the suspension was filtered. The filtrate was purified by silica gel column chromatography. Thus, 724 mg of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3: 2).

(e) tert-Butyl-4- [7- (2-chlorophenyl) -3- (2,2-dimethylpropionyloxymethyl) -1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl] piperazine-1-carboxylate

724 mg of [7- (2-chlorophenyl) -1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl-2,2-dimethylpropionate are suspended in 15 ml of N, N- dimethylformamide and 760 mg of N-chlorosuccinimide are added to the suspension. The reaction solution was stirred overnight and then diluted with ethyl acetate. The resulting solution was washed with water and 1 N. hydrochloric acid, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated. Thus, 764 mg of [8-chloro-7- (2-chlorophenyl) -1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl-2,2-dimethylpropionate is obtained. The resulting material was mixed with 4 g of tert-butylpiperazine-1-carboxylate. The mixture is heated at 150 ° C and stirred for three hours. Ethyl acetate and water are added to the reaction mixture, whereby the mixture is separated into layers. The organic layer is washed with 1 N. hydrochloric acid solution and dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography. Thus, 724 mg of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3: 2).

(f) tert-Butyl-4- [7- (2-chlorophenyl) -1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl] piperazin-1- carboxylate

tert-Butyl-4- [7- (2-chlorophenyl) -3- (2,2-dimethylpropionyloxymethyl) -1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8 -yl] piperazine-1-carboxylate was dissolved in a mixture of 10 ml of methanol and 20 ml of tetrahydrofuran, and 200 mg of sodium hydride was added to the mixture. The resulting mixture was stirred at room temperature overnight. To the reaction solution was added 1N. hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated. The residue was suspended in ether and the mixture was filtered. Thus, 450 mg of the title compound is obtained.

¹ H-NMR (DMSO-d ₆ )

δ 1.35 (s, 9H), 3.04 (s, 3H), 3.06-3.12 (m, 4H), 3.17-3.22 (m, 4H), 7.48 (dt , J = 1.6, 7.6 Hz, 1H), 7.53 (dt, J = 2.0, 7.6 Hz, 1H), 7.63 (dd, J = 2.0, 8.0 Hz, 1H), 7.65 (dd, J = 1.6, 8.0 Hz, 1H).

(g) tert-Butyl-4- [2-chloro-7- (2-chlorophenyl) -1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate ( g-1) and tert-butyl-4- [2,6-dichloro-7- (2-chlorophenyl) -7H-purin-8-yl] piperazine-1-carboxylate (g-2)

78 mg of tert-butyl 4- [7- (2-chlorophenyl) -1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl] piperazine-1-carboxylate dissolved in 3 ml of phosphorus oxychloride and the resulting mixture was stirred at 120 ° C overnight. The reaction solution was concentrated and the residue was dissolved in 1 ml of tetrahydrofuran. The solution was poured into a suspension of 50 mg of di-tert-butyl dicarbonate, 1 ml of tetrahydrofuran and 0.5 ml of water containing 100 mg of sodium bicarbonate. The reaction mixture was stirred at room temperature for three hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography. Thus, from the fraction eluted with hexane-ethyl acetate (3: 2), 16 mg of tert-butyl-4- [2,6-dichloro-7- (2-chlorophenyl) -7H-purin-8-yl] piperazine- are obtained 1-carboxylate, and from the fraction eluted with hexane-ethyl acetate (1: 9), 10 mg of tert-butyl-4- [2-chloro-7- (2-chlorophenyl) -1-methyl-6-oxo-6 , 7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate.

(h) Ethyl [7- (2-chlorophenyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] acetate trifluoroacetate

10 mg of tert-butyl-4- [2-chloro-7- (2-chlorophenyl) -1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate and 10 mg of ethyl glycolate is dissolved in 0.2 ml of N-methylpyrrolidone and 10 mg of sodium hydride is added to the resulting solution. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and the mixture was washed with 1 N. hydrochloric acid. Thus, 24 mg of tert-butyl-4- [7- (2-chlorophenyl) -2-ethoxycarbonylmethoxy-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazin-1- carboxylate. 8 mg of the obtained compound was dissolved in trifluoroacetic acid, and the resulting mixture was concentrated. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.11 mg of the title compound.

MS m / e (ESI) 447 (MH ⁺ -CF ₃ COOH).

Example 2

[7- (2-Chlorophenyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] acetate trifluoroacetate

16 mg of tert-butyl-4- [7- (2-chlorophenyl) -2-ethoxycarbonylmethoxy-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is mixed with 0.4 ml of methanol and 0.1 ml of 5 N. an aqueous solution of sodium hydroxide and the resulting mixture was allowed to stand at room temperature for two hours. To the reaction solution was added 1N. hydrochloric acid. The acidified solution is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated and the resulting residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.45 mg of the title compound.

MS m / e (ESI) 419 (MH ⁺ -CF ₃ COOH).

Example 3

[7- (2-Chlorophenyl) -2-cyclobutyloxy-8- (piperazin-1-yl) -1,7-dihydropurin-6-one

(a) [7-Benzyl-3- (2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl] methyl-2,2-dimethylpropionate

9.54 g of 7-benzylxanthine was dissolved in 250 ml of N, N-dimethylformamide and 17 g of potassium carbonate and 14.2 ml of chloromethyl pivalate were added to the resulting solution. The mixture was stirred at 50 ° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water and 1 N. hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. Thus, from the fraction eluted with hexane-ethyl acetate (3: 2), 12.8 g of the title compound are obtained.

(b) [3- (2,2-Dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl] methyl 2,2-dimethylpropionate

The title compound was obtained by treating [7-benzyl-3- (2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl] methyl 2,2-dimethylpropionate with the method used in example (1c).

(c) [7- (2-Chlorophenyl) -3- (2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl] methyl-2,2-dimethylpropionate

The title compound was prepared by treating [3- (2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl] methyl 2,2-dimethylpropionate according to the method used in example (1d).

¹ H-NMR (CDCl ₃ )

δ 1.16 (s, 9H), 1.22 (s, 9H), 5.99 (s, 2H), 6.19 (s, 2H), 7.42-7.52 (m, 3H), 7.58-7.61 (m, 1H); 7.73 (s, 1H).

(d) tert-Butyl-4- [7- (2-chlorophenyl) -1,3-bis- (2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl] piperazine-1-carboxylate

The title compound was obtained by treating [7- (2-chlorophenyl) -3- (2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl] methyl 2,2 -dimethylpropionate according to the method used in example (1e).

¹ H-NMR (CDCl ₃ )

δ 1.16 (s, 9H), 1.23 (s, 9H), 1.44 (s, 9H), 3.20-3.35 (m, 4H), 3.32-3.37 (m , 4H), 5.92 (s, 2H), 6.09 (s, 2H), 7.41-7.49 (m, 2H), 7.52-7.57 (m, 2H).

(e) t ret-Butyl-4- [7- (2-chlorophenyl) -1- (2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8 -yl] piperazine-1-carboxylate

2.227 g of tert-butyl-4- [7- (2-chlorophenyl) -1,3-bis (2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydro-1H-purine- 8-yl] piperazin-1-carboxylate is dissolved in a mixture of 10 ml of tetrahydrofuran and 20 ml of methanol, then 0.518 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene is added to the solution. The mixture was stirred at room temperature overnight. To the mixture is added 1 N. hydrochloric acid and precipitated solid are collected by filtration. The solid material was dried to give 1.025 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.16 (s, 9H), 1.44 (s, 9H), 3.22-3.24 (m, 4H), 3.33-3.35 (m, 4H), 5.90 (s , 2H), 7.43-7.47 (m, 2H), 7.51-7.57 (m, 2H), 8.71 (br, 1H).

(f) 7- (2-Chlorophenyl) -2-cyclobutyloxy-8- (piperazin-1-yl) -1,7-dihydropurin-6-one

8 mg tert-butyl-4- [7- (2-chlorophenyl) -1- (2,2-dimethylpropionyloxymethyl) -2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl ] piperazine-1-carboxylate is dissolved in 0.3 ml of N, N-dimethylformamide, and 0.05 ml of bromocyclobutane and 20 mg of potassium carbonate are added to the resulting solution. The resulting mixture was stirred at 50 ° C. overnight. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with water. The organic layer is concentrated. The residue was dissolved in methanol and 5 mg of sodium hydride was added to the solution. The resulting mixture was stirred at room temperature for three hours. The reaction mixture was neutralized with 1 N. hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 1.89 mg of the title compound.

MS m / e (ESI) 375 (MH ⁺ -CF ₃ COOH).

Example 4

Trifluoroacetate methyl 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] phenylacetate

(a) [7- (2-Butynyl) -1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl-2,2-dimethylpropionate

1.871 g of [1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl-2,2-dimethylpropionate are dissolved in 30 ml of N, N-dimethylformamide and 1 is added to the resulting solution, 5 g of potassium carbonate and 0.7 ml of 2-butynyl bromide. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and 1 N. hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. Thus, 2.12 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3: 2).

(b) 7- (2-Butynyl) -1-methyl-3,7-dihydropurin-2,6-dione

The title compound was obtained by treating [7- (2-butynyl) -1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl-2,2-dimethylpropionate according to the method, used in example (1f).

¹ H-NMR (CDCl ₃ )

δ 1.91 (t, J = 2.4 Hz, 3H), 3.39 (s, 3H), 5.10 (s, 2H), 7.93 (s, 1H), 10.62 (s, 1H).

(c) tert-Butyl 4- [7- (2-butynyl) -1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl] piperazine-1-carboxylate

The title compound was obtained by treating 7- (2-butynyl) -1-methyl-3,7-dihydropurin-2,6-dione according to the method used in Example (1e).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.83 (t, J = 2.4 Hz, 3H), 3.37 (s, 3H), 3.37-3.39 (m, 4H), 3, 58-3.60 (m, 4H), 4.87 (s, 2H), 9.68 (s, 1H).

(d) Methyl 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] phenylacetate trifluoroacetate

8 mg tert-butyl 4- [7- (2-butynyl) -1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl] piperazine-1-carboxylate and 10 mg of methyl 2-bromophenyl acetate was dissolved in 0.2 ml of N, N-dimethylformamide, and 10 mg of potassium carbonate was added to the resulting solution. The mixture was stirred at 50 ° C. overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and 1N. hydrochloric acid. The organic layer is concentrated. The residue was dissolved in trifluoroacetic acid, and the resulting mixture was concentrated. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.07 mg of the title compound.

MS m / e (ESI) 451 (MH ⁺ -CF ₃ COOH).

Example 5

7- (2-Butynyl) -2-cyclohexyloxy-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using iodocyclohexane instead of methyl 2-bromophenylacetate in Example (4d) and following the method of Example 4, the title compound was obtained.

MS m / e (ESI) 385 (MH ⁺ -CF ₃ COOH).

Example 6

7- (2-Butynyl) -2- (2-butoxy) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using 2-bromobutane instead of methyl-2-bromophenylacetate in Example (4d) and following the method of Example 4, the title compound is obtained.

MS m / e (ESI) 359 (MH ⁺ -CF ₃ COOH).

Example 7

7- (2-Butynyl) -2-cyclopentyloxy-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using bromocyclopentane instead of methyl 2-bromophenyl acetate in Example (4d) and following the method of Example 4, the title compound is obtained.

MS m / e (ESI) 371 (MH ⁺ -CF ₃ COOH).

Example 8

Ethyl 7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] butanoate trifluoroacetate

Using ethyl 2-bromobutanoic acid instead of methyl 2-bromophenyl acetate in Example (4d), following the method of Example 4, the title compound was obtained.

MS m / e (ESI) 417 (MH ⁺ -CF ₃ COOH).

Example 9

Ethyl 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] propionate

Using ethyl 2-bromopropionate instead of methyl 2-bromophenyl acetate in Example (4d), following the method of Example 4, the trifluoroacetate of the title compound was obtained. The resulting compound was chromatographed using NH-silica gel (silica gel whose surface is modified by amino groups, Fuji Silysia Chemical Ltd. NH-DM 2035). The title compound was obtained from the fraction eluted with ethyl acetate-methanol (20: 1).

MS m / e (ESI) 404 (MH ⁺ ).

Example 10

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] propionic acid trifluoroacetate

8 mg tert-butyl 4- [7- (2-butynyl) -1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl] piperazine-1-carboxylate and 10 mg of ethyl 2-bromopropionate was dissolved in 0.2 ml of N, N-dimethylformamide, and 10 mg of potassium carbonate was added to the resulting solution. The mixture is stirred overnight at 50 ° C. Ethyl acetate was added to the reaction solution, and the resulting mixture was washed with water and 1N. hydrochloric acid. The organic layer was concentrated to give tert-butyl-4- [7- (2-butynyl) -2- (1-carboxyethoxy) -1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate. This compound was dissolved in 0.4 ml of ethanol, and 0.1 ml of 5 N was added to the resulting solution. an aqueous solution of sodium hydroxide. The mixture was stirred at room temperature for 3 hours. To the solution is added 1 N. hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.37 mg of the title compound.

MS m / e (ESI) 375 (MH ⁺ -CF ₃ COOH).

Example 11

7- (2-Butynyl) -2-methoxy-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

(a) tert-Butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate ( a-1) and tert-butyl-4- [7- (2-butynyl) -2,6-dichloro-7H-purin-8-yl] piperazine-1-carboxylate (a-2)

5.127 g of tert-butyl-4- [7- (2-butynyl) -1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl] piperazine-1-carboxylate dissolved in 75 ml of phosphorus oxychloride and then the mixture is stirred at 120 ° C overnight. The reaction solution was concentrated and the residue was dissolved in 50 ml of tetrahydrofuran. The resulting solution was poured into a suspension of 7 g of di-tert-butyl dicarbonate, 50 ml of tetrahydrofuran, 100 g of sodium bicarbonate and 200 ml of water, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography. Thus, from the fraction eluted with hexane: ethyl acetate (1: 1), 1.348 g of tert-butyl-4- [7- (2-butynyl) -2,6-dichloro-7H-purin-8-yl] piperazine- are obtained 1-carboxylate [ ¹ H-NMR (CDCl ₃ ) δ 1.50 (s, 9H), 1.87 (t, J = 2.4 Hz, 3H), 3.64 (m, 8H), 4.81 (q, J = 2.4 Hz, 2H)], and from the fraction eluted with hexane-ethyl acetate (1: 9), 1.238 g of tert-butyl-4- [7- (2-butynyl) -2-chloro are obtained -1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate [ ¹ H-NMR (CDCl ₃ ) δ 1.49 (s, 9H), 1.83 (t, J = 2.4 Hz, 3H), 3.42-3.44 (m, 4H), 3.59-3.62 (m, 4H), 3.73 (s, 3H), 4, 93 (q, J = 2.4 Hz, 2H)].

(b) 7- (2-Butynyl) -2-methoxy-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of methanol and 10 mg of sodium hydride is added to the resulting solution. The resulting mixture was stirred at room temperature for 1 hour. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.72 mg of the title compound.

MS m / e (ESI) 317 (MH ⁺ -CF ₃ COOH).

Example 12

7- (2-Butynyl) -2-ethoxy-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one

Following the method of Example 11 and using ethanol instead of methanol in Example (11b), the trifluoroacetate of the title compound was obtained. The resulting compound was chromatographed using NH-silica gel. Thus, the title compound was obtained from the fraction eluted with ethyl acetate-methanol (20: 1).

¹ H-NMR (CDCl ₃ )

δ 1.42 (t, J = 7.2 Hz, 3H), 1.82 (t, J = 2.4 Hz, 3H), 3.02-3.06 (m, 4H), 3.40- 3.42 (m, 4H), 3.46 (s, 3H), 4.51 (q, J = 7.2 Hz, 2H), 4.90 (q, J = 2.4 Hz, 2H).

MS m / e (ESI) 331 (MH ⁺ ).

Example 13

Ethyl- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] acetate

Example 14

[7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] acetic acid

Ethyl [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] acetate trifluoroacetate and trifluoroacetate [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] acetic acid [MS m / e (ESI) 361 ( MH ⁺ -CF ₃ COOH)] is obtained by treating tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl ] piperazine-1-carboxylate with ethyl 2-hydroxyacetate, instead of ethanol, following the method described in example 11. Ethyl [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazine-1-) trifluoroacetate il) -6,7-dihydro-1H-purin-2-yloxy] acetate is subjected to chromatographic purification with Using NH-silica gel. Thus, ethyl- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7- is obtained from the fraction eluted with ethyl acetate-methanol (20: 1). dihydro-1H-purin-2-yloxy] acetate [ ¹ H-NMR (CDCl ₃ ) δ 1.29 (t, J = 7.2 Hz, 3H), 1.83 (t, J = 2.4 Hz, 3H), 3.02-3.06 (m, 4H), 3.38-3.41 (m, 4H), 3.55 (s, 3H), 4.22 (q, J = 7.2 Hz , 2H), 4.90 (q, J = 2.4 Hz, 2H), 5.03 (s, 2H). MS m / e (ESI) 389 (MH ⁺ )].

Example 15

7- (2-Butynyl) -2- (2-methoxyethoxy) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Following the method described in Example 13, using 2-methoxyethanol instead of ethyl 2-hydroxyacetate, the title compound was obtained.

MS m / e (ESI) 361 (MH ⁺ -CF ₃ COOH).

Example 16

Ethyl 1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] cyclopropanecarboxylate

Using ethyl 1-hydroxycyclopropanecarboxylate instead of ethyl 2-hydroxyacetate in Example 13, following the method described in this Example, trifluoroacetate of the title compound was obtained. The resulting compound was chromatographed using NH-silica gel. The title compound was obtained from the fraction eluted with ethyl acetate-methanol (20: 1).

¹ H-NMR (CDCl ₃ )

δ 1.19 (t, J = 7.2 Hz, 3H), 1.39-1.42 (m, 2H), 1.67-1.71 (m, 2H), 1.83 (t, J = 2.4 Hz, 3H), 3.02-3.05 (m, 4H), 3.37-3.40 (m, 4H), 3.49 (s, 3H), 4.14 (q, J = 7.2 Hz, 2H); 4.90 (q, J = 2.4 Hz, 2H).

MS m / e (ESI) 415 (MH ⁺ ).

Example 17

1- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] cyclopropanecarboxylic acid trifluoroacetate

20 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate and 20 mg of ethyl 1-hydroxycyclopropanecarboxylate was dissolved in 20 ml of N-methylpyrrolidone and 10 mg of sodium hydride was added to the resulting solution. The mixture was stirred at room temperature overnight. To the reaction solution was added 1N. hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated to give 63 mg of tert-butyl-4- [7- (2-butynyl) -2- (1-ethoxycarbonylcyclopropyloxy) -1-methyl-6-oxo-6,7-dihydro-1H-purine-8- yl] piperazine-1-carboxylate. The resulting compound is dissolved in a solution consisting of 0.4 ml of ethanol and 0.1 ml of 5 N. an aqueous solution of sodium hydroxide, and the resulting mixture was stirred at 50 ° C overnight. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated to obtain 22 mg of tert-butyl-4- [7- (2-butynyl) -2- (1-carboxycyclopropyloxy) -1-methyl-6-oxo-6,7-dihydro-1H-purine-8- yl] piperazine-1-carboxylate. 11 mg of the obtained compound was dissolved in trifluoroacetic acid, and the resulting mixture was concentrated. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 1.64 mg of the title compound.

MS m / e (ESI) 387 (MH ⁺ -CF ₃ COOH).

Example 18

Trifluoroacetate 1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] cyclopropanecarboxamide

11 mg tert-butyl-4- [7- (2-butynyl) -2- (1-carboxycyclopropyloxy) -1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazin-1 β-carboxylate is dissolved in 1 ml of tetrahydrofuran and 0.05 ml of triethylamine and 0.05 ml of ethyl chlorocarbonate are added. The resulting mixture was stirred at room temperature for 15 minutes. 0.1 ml of a 20% aqueous ammonia solution was added to the solution, and the resulting mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The resulting mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 1.18 mg of the title compound.

MS m / e (ESI) 386 (MH ⁺ -CF ₃ COOH).

Example 19

7- (2-Butynyl) -1-methyl-2- (2-oxotetrahydrofuran-3-yloxy) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using 3-hydroxy dihydrofuran-2-one instead of ethyl 2-hydroxyacetate and following the method described in Example 13, the title compound is obtained.

MS m / e (ESI) 387 (MH ⁺ -CF ₃ COOH).

Example 20

7- (2-Butynyl) -1-methyl-2-phenoxy-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using phenol instead of ethyl 2-hydroxyacetate in Example 13 and following the method described in this Example, the title compound is obtained.

MS m / e (ESI) 379 (MH ⁺ -CF ₃ COOH).

Example 21

Ethyl [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] acetate trifluoroacetate

Using ethyl 2- (tert-butoxycarbonyl) acetate instead of ethyl 2-hydroxyacetate in Example 13 and following the method described in this method, the title compound is obtained.

MS m / e (ESI) 373 (MH ⁺ -CF ₃ COOH).

Example 22

7- (2-Butynyl) -1,2-dimethyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate and 2 mg tetrakis (triphenylphosphine) palladium is dissolved in 0.2 ml of dioxane and 0.2 ml of methylzinc chloride (1.5 M solution in tetrahydrofuran) is added to the resulting solution. The resulting mixture was stirred at 50 ° C for 0.5 hours. The reaction solution was concentrated and the residue was dissolved in trifluoroacetic acid. The resulting mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.56 mg of the title compound.

MS m / e (ESI) 301 (MH ⁺ -CF ₃ COOH).

Example 23

7- (2-Butynyl) -1-methyl-2-butyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate and 2 mg tetrakis (triphenylphosphine) palladium is dissolved in 0.2 ml of dioxane and 0.3 ml of a solution obtained from 0.5 ml of butylmagnesium chloride (2.0 M solution in diethyl ether) and 2 ml of zinc chloride are added to the resulting solution (0, 5 M solution in tetrahydrofuran). The resulting mixture was stirred at 50 ° C for five hours. The reaction solution was concentrated and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.38 mg of the title compound.

MS m / e (ESI) 343 (MH ⁺ -CF ₃ COOH).

Example 24

7- (2-Butynyl) -1-methyl-2-benzyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

The title compound was prepared using a mixed solution of 0.5 ml of benzyl magnesium chloride (2.0 M solution in diethyl ether) and 2 ml of zinc chloride (0.5 M solution in tetrahydrofuran), following the method described in Example 23 .

MS m / e (ESI) 377 (MH ⁺ -CF ₃ COOH).

Example 25

7- (2-Butynyl) -1-methyl-2- (2-phenylethyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

The title compound was prepared using a mixed solution obtained from 0.5 ml of phenethyl magnesium chloride (2.0 M solution in diethyl ether) and 2 ml of zinc chloride (0.5 M solution in tetrahydrofuran), following the method described in example 23 .

MS m / e (ESI) 391 (MH ⁺ -CF ₃ COOH).

Example 26

7- (2-Butynyl) -1-methyl-2-phenyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

10 mg tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate, 2 mg tetrakis (triphenylphosphine) palladium and 20 mg phenyltributyltin are dissolved in 0.2 ml of dioxane and the resulting mixture is stirred at 80 ° C for 5 hours. The reaction solution was concentrated and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.62 mg of the title compound.

MS m / e (ESI) 363 (MH ⁺ -CF ₃ COOH).

Example 27

7- (2-Butynyl) -1-methyl-2-amino-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of a 20% aqueous ammonia solution and the resulting mixture was stirred at 80 ° C for 5 hours. The reaction solution was concentrated and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.82 mg of the title compound.

MS m / e (ESI) 302 (MH ⁺ -CF ₃ COOH).

Example 28

7- (2-Butynyl) -1-methyl-2-methylamino (8-piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of a 40% aqueous solution of methylamine and the resulting mixture was stirred at 80 ° C for 5 hours. The reaction solution was concentrated and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 6.95 mg of the title compound.

MS m / e (ESI) 316 (MH ⁺ -CF ₃ COOH).

Example 29

7- (2-Butynyl) -1-methyl-2-dimethylamino-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of a 40% aqueous solution of dimethylamine and the resulting mixture was stirred at 80 ° C for 5 hours. The reaction solution was concentrated and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 6.95 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.82 (t, J = 2.4 Hz, 3H), 2.83 (s, 6H), 3.02-3.05 (m, 4H), 3.39-3.42 (m, 4H ), 3.56 (s, 3H), 4.90 (d, J = 2.4 Hz, 2H).

MS m / e (ESI) 330 (MH ⁺ -CF ₃ COOH).

Example 30

Ethyl [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] acetate trifluoroacetate

10 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, and 15 mg of glycine ethyl ester hydrochloride and 50 μl of triethylamine are added to the resulting solution. The mixture is stirred at 80 ° C for 12 hours. Then the reaction solution was concentrated by flushing it with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the solution was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 7.60 mg of the title compound.

MS m / e (ESI) 388 (MH ⁺ -CF ₃ COOH).

Example 31

[7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] acetic acid trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, and 15 mg of glycine tert-butyl ether hydrochloride and 50 μl of triethylamine are added to the resulting solution. After stirring the resulting mixture at 80 ° C for 12 hours, the reaction solution was concentrated by purging with nitrogen gas. The resulting residue was dissolved in 0.40 ml of trifluoroacetic acid, and the solution was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 2.36 mg of the title compound.

MS m / e (ESI) 360 (MH ⁺ -CF ₃ COOH).

Example 32

Ethyl [N- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] methylamino] acetic trifluoroacetate acid

Using N-methylglycine ethyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, following the method described in this example, 2.06 mg of the title compound was obtained.

MS m / e (ESI) 402 (MH ⁺ -CF ₃ COOH).

Example 33

Methyl (S) -1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl trifluoroacetate] pyrrolidine 2-carboxylate

Using L-proline methyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, following the method described in this example, 1.35 mg of the title compound are obtained.

MS m / e (ESI) 414 (MH ⁺ -CF ₃ COOH).

Example 34

[N- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] methylamino] acetic acid trifluoroacetate

Using N-methylglycine tert-butyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, following the method described in this example, 3.16 mg of the title compound was obtained.

MS m / e (ESI) 374 (MH ⁺ -CF ₃ COOH).

Example 35

Methyl- (R) -1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl trifluoroacetate] pyrrolidine 2-carboxylate

Using D-proline methyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, following the method described in this example, 0.74 mg of the title compound was obtained.

MS m / e (ESI) 414 (MH ⁺ -CF ₃ COOH).

Example 36

Methyl 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] propionate trifluoroacetate

Using DL-alanine methyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, following the method described in this example, 1.20 mg of the title compound was obtained.

MS m / e (ESI) 388 (MH ⁺ -CF ₃ COOH).

Example 37

Methyl 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] -2-methylpropionate trifluoroacetate

Using methyl 2-aminoisobutylate hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, following the method described in this example, 1.18 mg of the title compound was obtained.

MS m / e (ESI) 402 (MH ⁺ -CF ₃ COOH).

Example 38

Ethyl (S) -2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino trifluoroacetate] propionate

Using L-alanine ethyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, following the method described in this example, 2.38 mg of the title compound are obtained.

MS m / e (ESI) 402 (MH ⁺ -CF ₃ COOH).

Example 39

(S) -2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] propionic acid trifluoroacetate

Using L-alanine tert-butyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, following the method described in this example, 0.76 mg of the title compound was obtained.

MS m / e (ESI) 374 (MH ⁺ -CF ₃ COOH).

Example 40

Ethyl 3- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] propionate trifluoroacetate

Using β-alanine ethyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, following the method described in this example, 0.85 mg of the title compound was obtained.

MS m / e (ESI) 402 (MH ⁺ -CF ₃ COOH).

Example 41

7- (2-Butynyl) -2- (2-ethoxyethylamino) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

10 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 20 μl of 2-ethoxyethylamine are added to the resulting solution. After the resulting mixture was stirred at 80 ° C for 12 hours, the reaction solution was concentrated by purging with nitrogen gas. The resulting residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 6.95 mg of the title compound.

MS m / e (ESI) 374 (MH ⁺ -CF ₃ COOH).

Example 42

7- (2-Butynyl) -1-methyl-2- (morpholin-4-yl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using morpholine instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 7.31 mg of the title compound was obtained.

MS m / e (ESI) 372 (MH ⁺ -CF ₃ COOH).

Example 43

2-Benzylamino-7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using benzylamine instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 8.40 mg of the title compound was obtained.

MS m / e (ESI) 392 (MH ⁺ -CF ₃ COOH).

Example 44

Ethyl 1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] piperidin-4- trifluoroacetate carboxylate

Using ethyl isonipecotate instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 7.43 mg of the title compound was obtained.

MS m / e (ESI) 442 (MH ⁺ -CF ₃ COOH).

Example 45

2- (N-benzylmethylamino) -7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using ethyl N-methylbenzylamine instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 2.38 mg of the title compound is obtained.

Mass spectrum m / e (ESI) 406 (MH ⁺ -CF ₃ COOH).

Example 46

7- (2-Butynyl) -2- (4-chlorobenzylamino) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using 4-chlorobenzylamine instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 2.84 mg of the title compound was obtained.

MS m / e (ESI) 426 (MH ⁺ -CF ₃ COOH).

Example 47

7- (2-Butynyl) -2- (4-methoxybenzylamino) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using 4-methoxybenzylamine, following the method described in Example 41, 3.77 mg of the title compound are obtained.

MS m / e (ESI) 422 (MH ⁺ -CF ₃ COOH).

Example 48

7- (2-Butynyl) -1-methyl-2- (2-phenylethylamino) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using phenethylamine instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 2.70 mg of the title compound was obtained.

MS m / e (ESI) 406 (MH ⁺ -CF ₃ COOH).

Example 49

7- (2-Butynyl) -1-methyl-2- [N- (2-phenylethyl) methylamino] -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using N-methylphenethylamine instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 2.17 mg of the title compound is obtained.

MS m / e (ESI) 420 (MH ⁺ -CF ₃ COOH).

Example 50

Ethyl 1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] piperidin-3- trifluoroacetate carboxylate

Using ethylnipecotate instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 2.93 mg of the title compound was obtained.

MS m / e (ESI) 442 (MH ⁺ -CF ₃ COOH).

Example 51

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (pyridin-2-ylmethylamino) -1,7-dihydropurin-6-one trifluoroacetate

Using 2-aminomethylpyridine instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 1.62 mg of the title compound was obtained.

MS m / e (ESI) 393 (MH ⁺ -CF ₃ COOH).

Example 52

Ethyl 1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] piperidin-2- trifluoroacetate carboxylate

Using ethylnipecotate instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 0.97 mg of the title compound was obtained.

MS m / e (ESI) 442 (MH ⁺ -CF ₃ COOH).

Example 53

Trifluoroacetate (S) -1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] pyrrolidin- 2-carboxylic acid

Using L-proline tert-butyl ether instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 4.07 mg of the title compound was obtained.

MS m / e (ESI) 400 (MH ⁺ -CF ₃ COOH).

Example 54

7- (2-Butynyl) -2-diethylamino-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using diethylamine instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 2.24 mg of the title compound is obtained.

MS m / e (ESI) 358 (MH ⁺ -CF ₃ COOH).

Example 55

7- (2-Butynyl) -2- (N-ethylmethylamino) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using N-ethylmethylamine instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 3.27 mg of the title compound was obtained.

MS m / e (ESI) 344 (MH ⁺ -CF ₃ COOH).

Example 56

Ethyl (R) -1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl trifluoroacetate] piperidine-3-carboxylate

Using ethyl- (R) -nipecotate instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 0.87 mg of the title compound is obtained.

MS m / e (ESI) 442 (MH ⁺ -CF ₃ COOH).

Example 57

Ethyl (S) -1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl trifluoroacetate] piperidine-3-carboxylate

Using ethyl (L) -nipecotate instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 2.94 mg of the title compound was obtained.

MS m / e (ESI) 442 (MH ⁺ -CF ₃ COOH).

Example 58

[N- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] methylamino] acetonitrile trifluoroacetate

Using methylaminoacetonitrile instead of 2-ethoxyethylamine in Example 41, following the method described in this example, 1.00 mg of the title compound are obtained.

MS m / e (ESI) 355 (MH ⁺ -CF ₃ COOH).

Example 59

7- (2-Butynyl) -2-isopropylamino-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 50 μl of isopropylamine are added to the resulting solution. The mixture was stirred at 60 ° C for 5 hours and then the reaction solution was concentrated by purging with nitrogen gas. The resulting residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by purging with nitrogen gas. The resulting residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.28 mg of the title compound.

MS m / e (ESI) 344 (MH ⁺ -CF ₃ COOH).

Example 60

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (pyridin-2-ylamino) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 50 μl of 2-aminopyridine are added to the resulting solution. The mixture is stirred at 110 ° C. for 12 hours and then concentrated by purging with nitrogen gas. The resulting residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by purging with nitrogen gas. The resulting residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.10 mg of the title compound.

MS m / e (ESI) 379 (MH ⁺ -CF ₃ COOH).

Example 61

7- (2-Butynyl) -1-methyl-2-phenylamino-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 100 μl of aniline is added to the resulting solution. The mixture is stirred at 110 ° C. for 12 hours and then concentrated by purging with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the resulting mixture was concentrated by purging with nitrogen gas. The resulting residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.23 mg of the title compound.

MS m / e (ESI) 378 (MH ⁺ -CF ₃ COOH).

Example 62

1- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] piperidine-3-carboxylic acid trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 20 μl of ethylnipecotate are added to the resulting solution. The mixture was stirred at 80 ° C for 12 hours and then concentrated by purging with nitrogen gas. The residue is dissolved in a solution consisting of 0.20 ml of ethanol and 0.20 ml of 5 N. an aqueous solution of sodium hydroxide. The mixture was stirred at room temperature for five hours and concentrated by purging with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the resulting mixture was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 1.92 mg of the title compound.

MS m / e (ESI) 414 (MH ⁺ -CF ₃ COOH).

Example 63

Trifluoroacetate (R) -1- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] pyrrolidin- 2-carboxylic acid

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, and 15 mg of D-proline methyl ester hydrochloride and 50 μl of triethylamine are added to the resulting solution. After stirring the resulting mixture at 80 ° C for 12 hours, the reaction solution was concentrated by purging with nitrogen gas. The residue is dissolved in a solution consisting of 0.20 ml of ethanol and 0.20 ml of 5 N. an aqueous solution of sodium hydroxide. The mixture was stirred at room temperature for five hours and then concentrated by purging with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the resulting mixture was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 3.42 mg of the title compound.

MS m / e (ESI) 400 (MH ⁺ -CF ₃ COOH).

Example 64

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] propionic acid trifluoroacetate

Using DL-alanine methyl ester hydrochloride instead of D-proline methyl ester hydrochloride in Example 63, following the method described in this example, 1.12 mg of the title compound was obtained.

MS m / e (ESI) 374 (MH ⁺ -CF ₃ COOH).

Example 65

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (pyridin-2-ylmethyloxy) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 25 mg of pyridin-2-ylmethanol and 5 mg of sodium hydride are added to the resulting solution. The mixture was stirred at room temperature for 5 hours, then concentrated by purging with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the resulting mixture was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.58 mg of the title compound.

MS m / e (ESI) 394 (MH ⁺ -CF ₃ COOH).

Example 66

7- (2-Butynyl) -2-isopropoxy-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 0.10 ml of isopropanol and 5 mg of sodium hydride are added to the resulting solution. After the mixture was stirred at room temperature for five hours, a saturated aqueous solution of ammonium chloride was added to the reaction solution. The resulting mixture was extracted with ethyl acetate. The organic layer is concentrated. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the resulting mixture was concentrated by purging with nitrogen gas. The resulting residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.68 mg of the title compound.

MS m / e (ESI) 345 (MH ⁺ -CF ₃ COOH).

Example 67

7- (2-Butynyl) -2- (2-butynyloxy) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using 2-butyn-1-ol instead of isopropanol in Example 66, following the method described in this Example, 3.40 mg of the title compound are obtained.

MS m / e (ESI) 355 (MH ⁺ -CF ₃ COOH).

Example 68

Trifluoroacetate methyl- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidine and 20 μl of methyl mercaptoacetate and 6 mg of potassium carbonate are added to the resulting solution. The solution was stirred at room temperature for five hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 0.40 ml of trifluoroacetic acid. The resulting mixture was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.83 mg of the title compound.

MS m / e (ESI) 391 (MH ⁺ -CF ₃ COOH).

Example 69

Ethyl 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] propionate trifluoroacetate

Using ethyl 2-mercaptopropionate instead of methyl mercaptoacetate, following the method described in Example 68, 4.30 mg of the title compound are obtained.

MS m / e (ESI) 419 (MH ⁺ -CF ₃ COOH).

Example 70

Ethyl 3- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] propionate trifluoroacetate

Using ethyl 3-mercaptopropionate instead of methyl mercaptoacetate in Example 68, following the method described in this example, 3.75 mg of the title compound are obtained.

MS m / e (ESI) 419 (MH ⁺ -CF ₃ COOH).

Example 71

7- (2-Butynyl) -2-ethylsulfanyl-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using ethanethiol instead of methyl mercaptoacetate in Example 68, following the method described in this example, 4.70 mg of the title compound was obtained.

MS m / e (ESI) 347 (MH ⁺ -CF ₃ COOH).

Example 72

7- (2-Butynyl) -2- (2-hydroxyethylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using 2-mercaptoethanol in place of methyl mercaptoacetate in Example 68, following the method described in this example, 3.57 mg of the title compound is obtained.

MS m / e (ESI) 363 (MH ⁺ -CF ₃ COOH).

Example 73

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (pyridin-2-ylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate

Using 2-mercaptopyridine instead of methyl mercaptoacetate in Example 68, following the method described in this example, 4.66 mg of the title compound are obtained.

MS m / e (ESI) 396 (MH ⁺ -CF ₃ COOH).

Example 74

7- (2-Butynyl) -1-methyl-2-methylsulfanyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using methyl mercaptan (30% methanol solution) instead of methyl mercaptoacetate in Example 68, following the method described in this example, 4.08 mg of the title compound was obtained.

MS m / e (ESI) 333 (MH ⁺ -CF ₃ COOH).

Example 75

7- (2-Butynyl) -2-cyclohexylsulfanyl-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using cyclohexanethiol instead of methyl mercaptoacetate in Example 68, following the method described in this example, 4.13 mg of the title compound was obtained.

MS m / e (ESI) 401 (MH ⁺ -CF ₃ COOH).

Example 76

7- (2-Butynyl) -2-isopropylsulfanyl-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 15 mg of propan-2-thiol sodium salt are added to the resulting solution. The resulting mixture was stirred at room temperature for five hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 0.40 ml of trifluoroacetic acid. The resulting mixture was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 4.56 mg of the title compound.

MS m / e (ESI) 361 (MH ⁺ -CF ₃ COOH).

Example 77

2-tert-butylsulfanyl-7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using the 2-methyl-2-propanethiol sodium salt in place of the propan-2-thiol sodium salt in Example 76, following the method described in this example, 2.58 mg of the title compound was obtained.

MS m / e (ESI) 375 (MH ⁺ -CF ₃ COOH).

Example 78

7- (2-Butynyl) -2-mercapto-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Example 79

[7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetic acid trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of N-methylpyrrolidone and 20 μl of methyl mercaptoacetate and 6 mg of potassium carbonate are added to the resulting solution. The resulting mixture was stirred at room temperature for five hours, and a saturated aqueous solution of ammonium chloride was added to the reaction solution. The resulting mixture was extracted with ethyl acetate. The organic layer is concentrated. The resulting residue was dissolved in a solution consisting of 0.20 ml of ethanol and 0.20 ml of 5 N. an aqueous solution of sodium hydroxide. The resulting mixture was stirred at room temperature overnight and then concentrated by purging with nitrogen gas. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the resulting solution was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.96 mg of 7- (2-butynyl) -2-mercapto-1 trifluoroacetate -methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one [MS m / e (ESI) 319 (MH ⁺ -CF ₃ COOH)] and 0.61 mg trifluoroacetate [7- ( 2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetic acid.

MS m / e (ESI) 377 (MH ⁺ -CF ₃ COOH).

Example 80

7- (2-Butynyl) -2-ethanesulfinyl-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 20 μl of ethanethiol and 6 mg of potassium carbonate are added to the resulting solution. The resulting mixture was stirred at room temperature for five hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer is concentrated. The residue was dissolved in 0.30 ml of dichloromethane and the resulting mixture was cooled to -78 ° C. 5 mg of m-chloroperbenzoic acid was added to the solution, and the mixture was stirred at -78 ° C for 15 minutes. A saturated aqueous solution of sodium sulfite was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer is concentrated. The residue was dissolved in 0.40 ml of trifluoroacetic acid, and the solution was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 3.21 mg of the title compound.

MS m / e (ESI) 363 (MH ⁺ -CF ₃ COOH).

Example 81

7- (2-Butynyl) -2-ethanesulfonyl-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 20 μl of ethanethiol and 6 mg of potassium carbonate are added to the resulting solution. The resulting mixture was stirred at room temperature for five hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer is concentrated. The residue was dissolved in 0.3 ml of dichloromethane and the resulting mixture was cooled to -78 ° C. 10 mg of m-chloroperbenzoic acid was added to the solution. The mixture is stirred at -78 ° C for 15 minutes and then at 0 ° C for 15 minutes. A saturated aqueous solution of sodium sulfite was added to the reaction solution, and the resulting mixture was extracted with dichloromethane. The organic layer is concentrated. The residue was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.19 mg of the title compound.

MS m / e (ESI) 379 (MH ⁺ -CF ₃ COOH).

Example 82

7- (2-Butynyl) -2-cyano-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of N-methylpyrrolidone and 10 mg of sodium cyanide are added to the resulting solution. The mixture is stirred at 50 ° C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to obtain 14 mg of tert-butyl-4- [7- (2-butynyl) -2-cyano-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazin- 1-carboxylate. 5 mg of this compound is dissolved in trifluoroacetic acid and the resulting solution is concentrated. The resulting residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.12 mg of the title compound.

MS m / e (ESI) 312 (MH ⁺ -CF ₃ COOH).

Example 83

7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carboxamide

(a) tert-Butyl-4- [7- (2-butynyl) -2-carbamoyl-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate

176 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 2 ml of N-methylpyrrolidone and 100 mg of sodium cyanide are added to the resulting solution. The mixture is stirred at 50 ° C for 0.5 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic layer was concentrated to give 170 mg of tert-butyl-4- [7- (2-butynyl) -2-cyano-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazin- 1-carboxylate. 98 mg of the obtained compound is dissolved in a mixture of 3 ml of tetrahydrofuran and 2 ml of methanol, and 0.5 ml of a 20% aqueous ammonia solution and 0.5 ml of a 30% aqueous hydrogen peroxide solution are added to the resulting solution. The resulting mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the resulting mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated under reduced pressure. The residue was chromatographed on a silica gel column. Thus, 77 mg of the title compound was obtained from the fraction eluted with ethyl acetate-methanol.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.83 (t, J = 1.2 Hz, 3H), 3.42-3.49 (m, 4H), 3.58-3.65 (m, 4H ), 3.95 (s, 3H), 5.01 (d, J = 2.4 Hz, 2H), 5.54 (br. 1H), 7.61 (br. 1H).

(b) 7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carboxamide

77 mg of tert-butyl-4- [7- (2-butynyl) -2-carbamoyl-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 1 ml of trifluoroacetic acid and the resulting solution was concentrated. The residue was subjected to chromatographic purification using NH-silica gel. Thus, 49 mg of the title compound was obtained from the fraction eluted with ethyl acetate-methanol (5: 1).

¹ H-NMR (CDCl ₃ )

δ 1.83 (t, J = 2.4 Hz, 3H), 3.05-3.07 (m, 4H), 3.45-3.48 (m, 4H), 3.94 (s, 3H ), 4.98 (s, 2H), 5.57 (br, 1H), 7.65 (br, 1H).

Example 84

7- (2-Butynyl) -2-carboxy-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Example 85

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

12.5 mg of tert-butyl-4- [7- (2-butynyl) -2-carbamoyl-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate dissolved in 0.3 ml of tetrahydrofuran and 0.2 ml of methanol and 0.05 ml of 2N are added to the resulting solution. sodium hydroxide solution. The mixture is stirred at 50 ° C for 2 hours. The reaction solution was concentrated and the residue was dissolved in trifluoroacetic acid. The resulting mixture was concentrated. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.44 mg of 7- (2-butynyl) -2-carboxy-1 trifluoroacetate -methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one [MS m / e (ESI) 331 (MH ⁺ -CF ₃ COOH)] and 6.4 mg of trifluoroacetate 7- (2 -butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one.

¹ H-NMR (CDCl ₃ )

δ 1.81 (t, J = 2.4 Hz, 3H), 3.54 (br, 4H), 3.63 (s, 3H), 3.83 (br, 4H), 5.02 ( s, 2H), 8.20 (s, 1H).

MS m / e (ESI) 287 (MH ⁺ -CF ₃ COOH).

Example 86

7- (2-Butynyl) -2-methoxy-1- (2-phenylethyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one hydrochloride

(a) [7-Benzyl-2,6-dioxo-1- (2-phenylethyl) -1,2,6,7-tetrahydropurin-3-yl] methyl 2,2-dimethylpropionate

Mixture consisting of 500 mg of [7-benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl] methyl-2,2-dimethylpropionate, 0.38 ml of 2-bromoethylbenzene, 390 mg of anhydrous potassium carbonate and 5 ml of N, N-dimethylformamide, stirred in an oil bath at 50 ° C for two hours. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 540 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.19 (s, 9H), 2.92-2.98 (m, 2H), 4.19-4.25 (m, 2H), 5.48 (s, 2H), 6.11 (s , 2H), 7.17-7.40 (m, 10H), 7.54 (s, 1H).

(b) [7- (2-Butynyl) -8-chloro-2,6-dioxo-1- (2-phenylethyl) -1,2,6,7-tetrahydropurin-3-yl] methyl-2,2- dimethyl propionate

Mixture of 540 mg of [7-benzyl-2,6-dioxo-1- (2-phenylethyl) -1,2,6,7-tetrahydropurin-3-yl] methyl-2,2-dimethylpropionate, 50 mg 10 % palladium on charcoal and 8 ml of acetic acid, stirred in a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered and then concentrated under reduced pressure to obtain 410 mg of a residue.

The residue was mixed with 0.15 ml of 1-bromo-2-butine, 300 mg of anhydrous potassium carbonate and 5 ml of N, N-dimethylformamide. The mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate and water. The organic layer was washed with water and then with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 470 mg of a residue.

The residue was mixed with 180 mg of N-chlorosuccinimide and 5 ml of N, N-dimethylformamide. The mixture was stirred at room temperature for 2 hours. After adding 0.5 ml of a 1 M aqueous solution of sodium thiosulfate, the reaction solution was extracted with ethyl acetate and water. The organic layer was washed with water and then with saturated brine. The organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Recrystallization from ethyl acetate-hexane gave 380 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.21 (s, 9H), 1.83 (t, J = 2 Hz, 3H), 2.92-2.98 (m, 2H), 4.19-4.25 (m, 2H), 5.11 (q, J = 2 Hz, 2H); 6.05 (s, 2H); 7.18-7.32 (m, 5H).

(c) tert-Butyl-4- [7- (2-butynyl) -2,6-dioxo-1- (2-phenylethyl) -2,3,6,7-tetrahydro-1H-purin-8-yl] piperazine-1-carboxylate

A mixture consisting of 380 mg of [7- (2-butynyl) -8-chloro-2,6-dioxo-1- (2-phenylethyl) -1,2,6,7-tetrahydropurin-3-yl] methyl 2, 2-dimethylpropionate, 460 mg of tert-butylpiperazine-1-carboxylate and 0.5 ml of N-methylpyrrolidone are stirred in an oil bath at 150 ° C for 15 minutes. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate-hexane (1: 1). The solution was filtered through a small amount of silica gel and then washed with ethyl acetate / hexane (1: 1). The filtrate is combined with the wash solution. The mixed solution was concentrated under reduced pressure to obtain 570 mg of a residue.

The residue is mixed with 5 ml of tetrahydrofuran and 2.5 ml of methanol. 33 mg of sodium hydride was added and the resulting mixture was stirred at room temperature for 30 minutes. 1 ml of 1N was added to the reaction solution. hydrochloric acid and the resulting mixture was extracted with ethyl acetate and water, then washed successively with water and saturated brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 350 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.85 (t, J = 2 Hz, 3H), 2.91-2.98 (m, 2H), 3.37 (br s, 4H), 3, 56-3.62 (m, 4H), 4.15-4.22 (m, 2H), 4.87 (q, J = 2 Hz, 2H), 7.18-7.35 (m, 5H) .

(d) tert-Butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-1- (2-phenylethyl) -6,7-dihydro-1H-purin-8-yl] piperazin- 1-carboxylate

A mixture consisting of 290 mg of tert-butyl-4- [7- (2-butynyl) -2,6-dioxo-1- (2-phenylethyl) -2,3,6,7-tetrahydro-1H-purin-8 -yl] piperazine-1-carboxylate and 4 ml of phosphorus oxychloride, heated and stirred in an oil bath at 120 ° C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 5 ml of tetrahydrofuran. The resulting solution was added dropwise to a stirred and ice-cooled mixture consisting of 250 mg of di-tert-butyl dicarbonate, 10 ml of a saturated sodium bicarbonate solution and 10 ml of tetrahydrofuran. The mixture was incubated at room temperature for 4 hours and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of 50% ethyl acetate in hexane. The resulting material was subjected to additional chromatographic purification on a reverse phase column, eluting with a mixture of 50-100% methanol-water, and 60 mg of the title compound was obtained.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.84 (t, J = 2 Hz, 3H), 3.10-3.16 (m, 2H), 3.40-3.46 (m, 2H), 3.57-3.63 (m, 4H), 4.42-4.49 (m, 4H), 4.94 (q, J = 2 Hz, 2H), 7.21-7.34 (m, 5H).

(e) 7- (2-Butynyl) -2-methoxy-1- (2-phenylethyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one hydrochloride

10 mg of sodium hydride (60%; oil) is added to a mixture of 7 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-1- (2-phenylethyl) -6 , 7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate and 0.5 ml of methanol. The mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then concentrated. 0.5 ml of trifluoroacetic acid was added to the residue. The resulting mixture was stirred at room temperature for 30 minutes and then concentrated. The resulting residue was purified on a chromatographic column with a reversible phase using a mixture of 20-80% methanol-water (containing 0.1% concentrated hydrochloric acid) to obtain 4.3 mg of the title compound.

¹ H-NMR (DMSO-d ₆ )

δ 1.80 (br s, 3H), 2.85 (t, J = 7 Hz, 2H), 3.28 (br s, 4H), 3.48-3.54 (m, 4H), 3.83 (s, 3H), 4.15 (t, J = 7 Hz, 2H), 4.97 (br s, 2H), 7.16-7.24 (m, 3H), 7.29 (t, J = 8 Hz, 2H), 9.08 (br s, 2H).

Example 87

7- (2-Butynyl) -2-ethoxy-1- (2-phenylethyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one hydrochloride

Using ethanol instead of methanol in Example 86 (e), following the method described in this Example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.28 (t, J = 7 Hz, 3H), 1.80 (s, 3H), 2.86 (t, J = 7 Hz, 2H), 3.27 (br.s, 4H), 3 , 46-3.53 (m, 4H), 4.15 (t, J = 7 Hz, 2H), 4.25 (q, J = 7 Hz, 2H), 4.97 (s, 2H), 7 , 17 (d, J = 7 Hz, 2H), 7.22 (t, J = 7 Hz, 1H), 7.29 (t, J = 7 Hz, 2H), 9.04 (br s, 2H )

Example 88

Methyl [7- (2-butynyl) -6-oxo-1- (2-phenylethyl) -8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate hydrochloride

Using methylthioglycolate instead of methanol and potassium carbonate as the base in Example 86 (e), following the method described in this example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.80 (s, 3H), 2.96 (t, J = 8 Hz, 2H), 3.29 (br s, 4H), 3.50-3.56 (m, 4H), 3, 68 (s, 3H), 4.16 (s, 2H), 4.23 (t, J = 8 Hz, 2H), 4.99 (s, 2H), 7.24-7.38 (m, 5H ), 8.96 (br s, 2H).

Example 89

Ethyl [7- (2-butynyl) -6-oxo-1- (2-phenylethyl) -8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] acetate hydrochloride

Using glycine ethyl ester hydrochloride instead of methanol and potassium carbonate as the base in Example 86 (e), following the method described in this Example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.22 (t, J = 7 Hz, 3H), 1.78 (s, 3H), 2.87 (t, J = 8 Hz, 2H), 3.26 (br.s, 4H), 3 47 (br.s, 4H), 4.05 (d, J = 6 Hz, 2H), 4.12 (q, J = 7 Hz, 2H), 4.21 (t, J = 8 Hz, 2H ), 4.89 (br s, 2H), 7.17-7.35 (m, 5H), 7.51 (t, J = 6 Hz, 1H), 8.93 (br s, 2H) .

Example 90

2- [7- (2-Butynyl) -6-oxo-1- (2-phenylethyl) -8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] acetamide hydrochloride

Using glycinamide hydrochloride instead of methanol and potassium carbonate as the base in Example 86 (e), following the method described in this example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.79 (s, 3H), 2.87 (t, J = 8 Hz, 2H), 3.26 (br s, 4H), 3.52 (br s, 4H), 3.84 ( d, J = 5 Hz, 2H), 4.19 (t, J = 8 Hz, 2H), 4.91 (s, 2H), 7.02 (s, 1H), 7.16-7.40 ( m, 7H), 9.08 (br s, 2H).

Example 91

Ethyl N- [7- (2-butynyl) -6-oxo-1- (2-phenylethyl) -8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl hydrochloride] N-methylaminoacetate

Using N-methylglycine ethyl ester hydrochloride instead of methanol and potassium carbonate as the base in Example 86 (e), following the method described in this example, the title compound was synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.17 (t, J = 7 Hz, 3H), 1.80 (s, 3H), 2.76 (s, 3H), 2.96 (t, J = 8 Hz, 2H), 3.28 (br.s, 4H), 3.46-3.52 (m, 4H), 3.88 (s, 2H), 4.09 (q, J = 7 Hz, 2H), 4.27 (t, J = 8 Hz, 2H), 4.98 (s, 2H), 7.15-7.30 (m, 5H), 8.95 (br s, 2H).

Example 92

Methyl [7- (2-butynyl) -6-oxo-1- (2-phenylethyl) -8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] acetate hydrochloride

Using methyl glycolate instead of methanol in Example 86 (e), following the method described in this Example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.80 (s, 3H), 2.93 (t, J = 8 Hz, 2H), 3.28 (br s, 4H), 3.49 (br s, 4H), 3.72 ( s, 3H), 4.20 (t, J = 8 Hz, 2H), 4.96 (s, 2H), 5.02 (s, 2H), 7.20-7.34 (m, 5H), 8.87 (br s, 2H).

Example 93

7- (2-Butynyl) -2- (2-hydroxyethoxy) -1- (2-phenylethyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one hydrochloride

Using ethylene glycol instead of methanol in Example 86 (e), following the method described in this Example, the title compound was synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.80 (s, 3H), 2.88 (t, J = 8 Hz, 2H), 3.29 (br s, 4H), 3.49 (br s, 4H), 3.71 ( t, J = 6 Hz, 2H), 4.18 (t, J = 8 Hz, 2H), 4.28 (t, J = 6 Hz, 2H), 4.97 (s, 2H), 7.16 -7.32 (m, 5H); 8.90 (br s, 2H).

Example 94

7- (2-Butynyl) -2-dimethylamino-1- (2-phenylethyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one hydrochloride

Using a 50% aqueous solution of dimethylamine instead of methanol in Example 86 (e), following the method described in this example, the title compound was synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.80 (s, 3H), 2.60 (s, 6H), 2.89 (t, J = 8 Hz, 2H), 3.28 (br s, 4H), 3.49 (br. s, 4H), 4.26 (t, J = 8 Hz, 2H), 4.98 (s, 2H), 7.06-7.27 (m, 5H), 8.93 (br s, 2H )

Example 95

7- (2-Butynyl) -2-chloro-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

(a) tert-Butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate

A mixture consisting of 1.0 g of tert-butyl-4- [7- (2-butynyl) -2,6-dichloro-7H-purin-8-yl] piperazine-1-carboxylate, 580 mg of sodium acetate and 10 ml dimethyl sulfoxide, stirred in an oil bath at 80 ° C for 24 hours. The reaction solution was extracted with ethyl acetate and water. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a mixture of 50-70% ethyl acetate / hexane and recrystallized from ethyl acetate-hexane to give 800 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.83 (t, J = 2 Hz, 3H), 3.44 (br s, 4H), 3.56-3.63 (m, 4H), 4, 94 (q, J = 2 Hz, 2H).

(b) 7- (2-Butynyl) -2-chloro-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

8 mg of tert-butyl 4- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in trifluoroacetic acid and the resulting the solution is concentrated. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 3.45 mg of the title compound.

MS m / e (ESI) 307 (MH ⁺ -CF ₃ COOH).

Example 96

2- [7- (2-Butynyl) -2-dimethylamino-6-oxo-8- (piperazin-1-yl) -6,7-dihydropurin-1-ylmethyl] benzonitrile hydrochloride

(a) tert-Butyl-4- [7- (2-butynyl) -2-chloro-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine- 1-carboxylate

Mixture consisting of 100 mg of tert-butyl 4- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate, 60 mg of 2-cyanobenzyl bromide, 68 mg of anhydrous potassium carbonate and 1 ml of N, N-dimethylformamide are stirred at room temperature for 4 hours. Ethyl acetate-hexane (1: 1) and water were added to the reaction solution. Insoluble material is removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of 30-50% ethyl acetate / hexane to give 50 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.83 (t, J = 2 Hz, 3H), 3.43-3.49 (m, 4H), 3.58-3.64 (m, 4H), 4.95 (q, J = 2 Hz, 2H), 5.72 (s, 2H), 7.06 (d, J = 8 Hz, 1H), 7.39 (t, J = 8 Hz, 1H) 7.51 (t, J = 8 Hz, 1H); 7.71 (d, J = 8 Hz, 1H).

(b) tert-Butyl-4- [7- (2-butynyl) -1- (2-cyanobenzyl) -2-dimethylamino-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine- 1-carboxylate

Mixture of 8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl ] piperazine-1-carboxylate, 20 μl of a 50% aqueous solution of dimethylamine and 0.2 ml of N, N-dimethylformamide are stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate and water. The organic layer was washed successively with water and saturated brine, and then concentrated. The resulting residue was purified by flash chromatography on silica gel using a mixture of 70% ethyl acetate / hexane to give 6.5 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.81 (t, J = 2 Hz, 3H), 2.73 (s, 6H), 3.38-3.45 (m, 4H), 3.56- 3.64 (m, 4H), 4.91 (q, J = 2 Hz, 2H), 5.55 (s, 2H), 7.07 (d, J = 8 Hz, 1H), 7.32 ( t, J = 8 Hz, 1H), 7.46 (t, J = 8 Hz, 1H), 7.65 (d, J = 8 Hz, 1H).

(c) 2- [7- (2-Butynyl) -2-dimethylamino-6-oxo-8- (piperazin-1-yl) -6,7-dihydropurin-1-ylmethyl] benzonitrile hydrochloride

6.5 mg tert-butyl-4- [7- (2-butynyl) -1- (2-cyanobenzyl) -2-dimethylamino-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine -1-carboxylate is dissolved in 0.5 ml of trifluoroacetic acid and the resulting mixture is allowed to stand at room temperature for 20 minutes. The reaction solution was concentrated and the residue was chromatographed on a reversible phase column using a mixture of 20-80% methanol and water (containing 0.1% concentrated hydrochloric acid) to obtain 6.4 mg of the title compound.

¹ H-NMR (DMSO-d ₆ )

δ 1.76 (s, 3H), 2.69 (s, 6H), 3.28 (br s, 4H), 3.51 (br s, 4H), 4.91 (s, 2H), 5.40 (s, 2H), 7.04 (d, J = 8 Hz, 1H), 7.43 (t, J = 8 Hz, 1H), 7.60 (t, J = 8 Hz, 1H) 7.83 (d, J = 8 Hz, 1H); 8.90 (br s, 2H).

Example 97

Methyl [7- (2-butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate hydrochloride

Using methylthioglycolate instead of dimethylamine and anhydrous potassium carbonate as the base in Example 96 (b), following the method described in Example 96, the title compound was synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.79 (s, 3H), 3.29 (br s, 4H), 3.56 (br s, 4H), 3.65 (s, 3H), 4.12 (s, 2H), 4.99 (s, 2H), 5.48 (s, 2H), 7.10 (d, J = 8 Hz, 1H), 7.50 (t, J = 8 Hz, 1H), 7.65 ( t, J = 8 Hz, 1H), 7.92 (d, J = 8 Hz, 1H), 8.95 (br s, 2H).

Example 98

2- [7- (2-Butynyl) -2-methoxy-6-oxo-8- (piperazin-1-yl) -6,7-dihydropurin-1-ylmethyl] benzonitrile hydrochloride

Using methanol instead of dimethylamine and anhydrous potassium carbonate as the base in Example 96 (b), following the method described in Example 96, the title compound was synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.79 (s, 3H), 3.28 (br s, 4H), 3.48-3.56 (m, 4H), 3.91 (s, 3H), 4.97 (s, 2H ), 5.32 (s, 2H), 7.19 (d, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 7.63 (t, J = 8 Hz, 1H), 7.87 (d, J = 8 Hz, 1H), 9.05 (br s, 2H).

Example 99

Methyl [7- (2-butynyl) -1-cyanomethyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate hydrochloride

(a) t ret-Butyl 4- [7- (2-butynyl) -2-chloro-1-cyanomethyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate

Using bromoacetonitrile instead of dimethylamine in Example 96 (b), following the method described in Example 96 (a), the title compound is synthesized.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.84 (t, J = 2 Hz, 3H), 3.43-3.49 (m, 4H), 3.58-3.63 (m, 4H), 4.91 (q, J = 2 Hz, 2H); 5.18 (s, 2H).

(b) Methyl [7- (2-butynyl) -1-cyanomethyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate hydrochloride

Using the compound obtained in Example 99 (a) above, instead of the compound obtained in Example 96 (a), following the method described in Example 97, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.80 (s, 3H), 3.29 (br s, 4H), 3.55 (br s, 4H), 3.68 (s, 3H), 4.22 (s, 2H), 4.98 (s, 2H); 5.21 (s, 2H); 8.93 (br s, 2H).

Example 100

Methyl [1,7-bis (2-butynyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate hydrochloride

(a) tert-Butyl-4- [1,7-bis (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate

Using 1-bromo-2-butine instead of 2-cyanobenzyl bromide in Example 96 (a), following the method described in Example 96 (a), the title compound was synthesized.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.80 (t, J = 2 Hz, 3H), 1.83 (t, J = 2 Hz, 3H), 3.40-3.45 (m, 4H) 3.57-3.62 (m, 4H), 4.93 (q, J = 2 Hz, 2H), 4.98 (q, J = 2 Hz, 2H).

(b) Methyl [1,7-bis (2-butynyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate hydrochloride

Using the compound obtained in Example 100 (a) above, instead of the compound obtained in Example 96 (a), following the method described in Example 97, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.79 (s, 6H), 3.28 (br s, 4H), 3.53 (br s, 4H), 3.67 (s, 3H), 4.15 (s, 2H), 4.83 (s, 2H); 4.98 (s, 2H); 9.02 (br s, 2H).

Example 101

1,7-bis (2-butynyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

Using sodium cyanide instead of methylthioglycolate in Example 100, following the method described in this Example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.81 (s, 3H), 1.82 (s, 3H), 3.28 (br s, 4H), 3.56-3.63 (m, 4H), 4.95 (q, J = 2 Hz, 2H), 5.07 (q, J = 2 Hz, 2H), 9.04 (br s, 2H).

Example 102

1,7-bis (2-butynyl) -2-methoxy-8- (piperazin-1-yl) -1,7-dihydropurin-6-one hydrochloride

Using methanol instead of methylthioglycolate and sodium hydride as the base in Example 100, following the method described in this Example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.75 (s, 3H), 1.80 (s, 3H), 3.28 (br s, 4H), 3.47-3.55 (m, 4H), 3.98 (s, 3H) ), 4.66 (s, 2H), 4.96 (s, 2H), 9.01 (br s, 2H).

Example 103

Methyl [1-allyl-7- (2-butynyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate hydrochloride

(a) tert-Butyl-4- [1-allyl-7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate

Using allyl bromide instead of 2-cyanobenzyl bromide in Example 96 (a), following the method described in this Example, the title compound is synthesized.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.83 (t, J = 2 Hz, 3H), 3.38-3.45 (m, 4H), 3.55-3.63 (m, 4H), 4.90 (d, J = 5 Hz, 2H), 4.93 (q, J = 2 Hz, 2H), 5.19-5.29 (m, 2H), 5.93 (ddt, J = 10 17.5 Hz, 1H).

(b) Methyl [1-allyl-7- (2-butynyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate hydrochloride

Using the compound described in Example 103 (a) above, instead of the compound obtained in Example 96 (a) in Example 97, following the method described in Example 97, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.79 (s, 3H), 3.27 (br s, 4H), 3.48-3.56 (m, 4H), 3.66 (s, 3H), 4.12 (s, 2H ), 4.70 (d, J = 5 Hz, 2H), 4.98 (br.s, 2H), 5.07 (d, J = 17 Hz, 1H), 5.21 (d, J = 10 Hz, 1H), 5.89 (DDT, J = 10, 17, 5 Hz, 1H), 9.07 (br s, 2H).

Example 104

1-allyl-7- (2-butynyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

The title compound was synthesized following the method of Example 103 using sodium cyanide instead of allyl bromide.

¹ H-NMR (DMSO-d ₆ )

δ 1.81 (t, J = 2 Hz, 3H), 3.29 (br.s, 4H), 3.57-3.64 (m, 4H), 4.81 (d, J = 5 Hz, 2H), 5.04-5.10 (m, 3H), 5.26 (d, J = 10 Hz, 1H), 6.00 (ddt, J = 10, 17, 5 Hz, 1H), 9, 12 (br s, 2H).

Example 105

1-allyl-7- (2-butynyl) -2-methoxy-8- (piperazin-1-yl) -1,7-dihydropurin-6-one hydrochloride

Using methanol instead of methylthioglycolate and sodium hydride as the base in Example 103, following the method described in this Example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.79 (t, J = 2 Hz, 3H), 3.27 (br s, 4H), 3.48-3.56 (m, 4H), 3.93 (s, 3H), 4, 55 (d, J = 5 Hz, 2H), 4.94-5.02 (m, 3H), 5.12 (d, J = 10 Hz, 1H), 5.87 (ddt, J = 10, 17 5 Hz, 1H); 9.04 (br s, 2H).

Example 106

Methyl [7- (2-butynyl) -1- (2-methoxyethyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetate hydrochloride

(a) tert-Butyl-4- [7- (2-butynyl) -1- (2-methoxyethyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazin- 1-carboxylate

Using 2-bromoethyl methyl ether instead of 2-cyanobenzyl bromide in Example 96 (a), following the method described in this Example, the title compound is synthesized.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.83 (t, J = 2 Hz, 3H), 3.36 (s, 3H), 3.39-3.45 (m, 4H), 3.56- 3.61 (m, 4H), 3.69 (t, J = 6 Hz, 2H), 4.50 (t, J = 6 Hz, 2H), 4.92 (q, J = 2 Hz, 2H) .

(b) Methyl [7- (2-butynyl) -1- (2-methoxyethyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl hydrochloride] acetate

Using the compound obtained in the above Example 106 (a), instead of the compound obtained in the Example 96 (a) used in Example 97, following the method described in the Example 97, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.80 (s, 3H), 3.25-3.32 (m, 7H), 3.50-3.55 (m, 4H), 3.61 (t, J = 6 Hz, 2H), 3.67 (s, 3H), 4.14 (s, 2H), 4.25 (t, J = 6 Hz, 2H), 4.98 (s, 2H), 9.00 (br s, 2H )

Example 107

7- (2-Butynyl) -1- (2-methoxyethyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

Using sodium cyanide instead of methylthioglycolate in Example 106, following the method described in this Example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.81 (s, 3H), 3.25 (s, 3H), 3.29 (br s, 4H), 3.55-3.64 (m, 6H), 4.34 (t, J = 5 Hz, 2H), 5.08 (s, 2H), 9.05 (br s, 2H).

Example 108

7- (2-Butynyl) -1- (2-methoxyethyl) -2-methoxy-8- (piperazin-1-yl) -1,7-dihydropurin-6-one hydrochloride

Using methanol instead of methylthioglycolate and anhydrous potassium carbonate as the base in Example 106, following the method described in this Example, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.79 (s, 3H), 3.23 (s, 3H), 3.27 (br s, 4H), 3.46-3.55 (m, 6H), 3.94 (s, 3H) ), 4.13 (t, J = 6 Hz, 2H), 4.96 (s, 2H), 9.03 (br s, 2H).

Example 109

7-Benzyl-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

(a) 7-Benzyl-1,7-dihydropurin-6-one

18.23 g of inosine are dissolved in 90 ml of dimethyl sulfoxide and 16 ml of benzyl bromide are added to the resulting solution. The mixture was stirred at room temperature overnight. The reaction solution was poured into 3 L of ethyl acetate. The resulting upper layer was removed and the lower oil layer was dissolved in 10% hydrochloric acid (135 ml). The solution is heated to 70 ° C and stirred for 4 hours. The solution was cooled to room temperature and then neutralized to pH 7 using 5 N. an aqueous solution of sodium hydroxide. The precipitated solid was collected by filtration and dried to obtain 12.748 g of the title compound.

(b) tert-Butyl 4- (7-benzyl-6-oxo-6,7-dihydro-1H-purin-8-yl) piperazine-1-carboxylate

12.748 g of 7-benzyl-1,7-dihydropurin-6-one is dissolved in 150 ml of N, N-dimethylformamide and 7.9 g of N-chlorosuccinimide are added to the resulting solution. The reaction solution was stirred overnight and diluted with ethyl acetate. The solution is washed with water and 1 N. hydrochloric acid and then dried over anhydrous magnesium sulfate. The solution was filtered and the filtrate was concentrated to obtain 6.103 g of 7-benzyl-8-chloro-1,7-dihydropurin-6-one. The resulting substance is mixed with 20 g of tert-butylpiperazine-1-carboxylate and the mixture is heated at 150 ° C. After stirring for one hour, the reaction mixture was partitioned between ethyl acetate and water. The organic layer is washed with 1 N. hydrochloric acid and dried over anhydrous magnesium sulfate. After filtration, the resulting material was concentrated. The residue was purified by silica gel column chromatography. Thus, 1.539 g of the title compound was obtained from the fraction eluted with ethyl acetate-methanol (10: 1).

¹ H-NMR (CDCl ₃ )

δ 1.39 (s, 9H), 3.07-3.10 (m, 4H), 3.35-3.39 (m, 4H), 5.44 (s, 2H), 7.16-7 18 (m, 2H), 7.22-7.32 (m, 3H), 7.91 (s, 1H), 12.18 (s, 1H).

(c) 7-Benzyl-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

15 mg of tert-butyl 4- (7-benzyl-6-oxo-6,7-dihydro-1H-purin-8-yl) piperazine-1-carboxylate was dissolved in 1 ml of N, N-dimethylformamide and was added to the resulting solution 10 mg sodium hydride and 10 μl methyl iodide. The resulting mixture was stirred at room temperature for 3 days, ethyl acetate and water were added, then the mixture was stratified. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The resulting solution was concentrated. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)), whereby 4.31 mg of the title compound was obtained.

MS m / e (ESI) 325 (MH ⁺ -CF ₃ COOH).

Example 110

7-Benzyl-1-ethyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

The title compound was prepared according to the method described in Example 109 using iodoethane instead of methyl iodide.

MS m / e (ESI) 339 (MH ⁺ -CF ₃ COOH).

Example 111

Ethyl [7-benzyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydropurin-1-yl] acetate trifluoroacetate

The title compound was prepared according to the method described in Example 109 using ethyl bromoacetate instead of methyl iodide.

MS m / e (ESI) 397 (MH ⁺ -CF ₃ COOH).

Example 112

7-benzyl-1- (2-methoxyethyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

The title compound was prepared according to the method described in Example 109 using 2-methoxyethyl bromide instead of methyl iodide.

MS m / e (ESI) 369 (MH ⁺ -CF ₃ COOH).

Example 113

Trifluoroacetate 7-benzyl-1- (2-propynyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one

The title compound was prepared according to the method described in Example 109 using propargyl bromide instead of methyl iodide.

MS m / e (ESI) 349 (MH ⁺ -CF ₃ COOH).

Example 114

7-Benzyl-1-cyanomethyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

The title compound was prepared according to the method described in Example 109 using bromoacetonitrile instead of methyl iodide.

MS m / e (ESI) 350 (MH ⁺ -CF ₃ COOH).

Example 115

3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) Ethyl 2-bromo-3- (2-butynyl) -5-cyano-3H-imidazole-4-carboxylate

4.56 ml of sulfuric acid is added to 170 ml of ethanol containing 16.80 g of 2-bromo-1H-imidazole-4,5-dicarbonitrile [CAS No. 50847-09-1], and the resulting mixture was refluxed for 48 hours. The solution is cooled and 500 ml of ethyl acetate and 200 ml of water are added to it. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide and 14.1 g of potassium carbonate and 8.6 ml of 2-butynyl bromide were added to the solution. The mixture was stirred at room temperature for 18 hours. 500 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 300 ml of water, then washed with 300 ml of a saturated sodium chloride solution. The resulting solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, from the fraction eluted with hexane-ethyl acetate (9: 1), 4.09 g of the title compound are obtained.

¹ H-NMR (CDCl ₃ )

δ 1.43 (t, J = 7.2 Hz, 3H), 1.81 (s, 3H), 4.47 (q, J = 7.2 Hz, 2H), 5.16 (s, 2H) .

(b) tert-Butyl-4- [1- (2-butynyl) -4-cyano-5-ethoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

4.09 g of 2-bromo-3- (2-butynyl) -5-cyano-3H-imidazole-4-carboxylic acid ethyl ester was combined with 7.70 g of tert-butylpiperazine-1-carboxylate and the resulting mixture was heated with stirring to 150ºС for 50 minutes. The reaction mixture was dissolved in toluene. After that, the mixture is subjected to purification by column chromatography on silica gel. Thus, 4.47 g of the title compound is obtained from the fraction eluted with hexane-ethyl acetate (2: 1).

¹ H-NMR (CDCl ₃ )

δ 1.43 (t, J = 7.2 Hz, 3H), 1.47 (s, 9H), 1.82 (t, J = 2.3 Hz, 3H), 3.08-3.13 ( m, 4H), 3.57-3.61 (m, 4H), 4.44 (q, J = 7.2 Hz, 2H), 4.89 (q, J = 2.3 Hz, 2H).

(c) tert-Butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-thiocarbamoyl-1H-imidazol-2-yl] piperazine-1-carboxylate

5 ml of a 50% aqueous solution of ammonium sulfide is added to 20 ml of an ethanol solution containing 0.80 g of tert-butyl-4- [1- (2-butynyl) -4-cyano-5-ethoxycarbonyl-1H-imidazol-2-yl ] piperazine-1-carboxylate, and the resulting mixture was heated at 60 ° C for 14 hours. To the resulting mixture were added 100 ml of ethyl acetate and 50 ml of water, then the organic layer was washed successively with 50 ml of water and 50 ml of a saturated solution of sodium chloride. Then the reaction solution is dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.58 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3: 2).

¹ H-NMR (CDCl ₃ )

δ 1.43 (t, J = 7.2 Hz, 3H), 1.48 (s, 9H), 1.82 (t, J = 2.3 Hz, 3H), 3.12-3.16 ( m, 4H), 3.54-3.59 (m, 4H), 4.44 (q, J = 7.2 Hz, 2H), 4.89 (q, J = 2.3 Hz, 2H), 7.41 (br s, 1H); 8.88 (br s, 1H).

(d) tert-Butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-methylsulfanylcarbonimidoyl-1H-imidazol-2-yl] piperazine-1-carboxylate

0.235 g of trimethyloxonium tetrafluoroborate is added to 20 ml of a dichloromethane solution containing 0.58 g of tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-thiocarbamoyl-1H-imidazol-2-yl] piperazin-1 β-carboxylate and the mixture was stirred at room temperature for 18 hours. To the resulting solution was added 50 ml of dichloromethane and the mixture was washed with 20 ml of a saturated sodium bicarbonate solution. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.55 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.41 (t, J = 7.2 Hz, 3H), 1.47 (s, 9H), 1.81 (t, J = 2.3 Hz, 3H), 2.39 (s, 3H) , 3.12-3.16 (m, 4H), 3.56-3.59 (m, 4H), 4.42 (q, J = 7.2 Hz, 2H), 4.80 (q, J = 2.3 Hz, 2H).

(e) tert-Butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-methylsulfanylcarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

5 ml 2 n. aqueous hydrochloric acid is added to 30 ml of an ethanol solution containing 0.55 g of tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-methylsulfanylcarbonimidoyl-1H-imidazol-2-yl] piperazin-1 -carboxylate, and the resulting mixture is heated at 60 ° C for 5 hours. After concentration under reduced pressure, 25 ml of ethyl acetate and 1N were added to the resulting solution. sodium hydroxide solution. The aqueous layer was extracted with 25 ml of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 10 ml of a saturated solution of sodium chloride containing 1 ml of 1 N. sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The resulting solution was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane and 0.10 ml of triethylamine and 0.256 g of di-tert-butyl dicarbonate were added to the resulting solution. The mixture was stirred at room temperature for 15 hours and then 25 ml of ethyl acetate was added thereto. The mixture is washed successively with 10 ml of 0.1 N. hydrochloric acid, 10 ml of a saturated solution of sodium bicarbonate and 10 ml of a saturated solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.15 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (4: 1).

¹ H-NMR (CDCl ₃ )

δ 1.43 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 1.81 (t, J = 2.3 Hz, 3H), 2.40 (s, 3H) , 3.16-3.20 (m, 4H), 3.55-3.59 (m, 4H), 4.35 (q, J = 7.1 Hz, 2H), 4.80 (q, J = 2.3 Hz, 2H).

(f) tert-Butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-hydroxymethyl-1H-imidazol-2-yl] piperazine-1-carboxylate

0.187 g of mercury (II) acetate and 0.090 g of sodium borohydride are added to 8 ml of an ethanol solution containing 0.265 g of tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-methylsulfanylcarbonyl-1H-imidazole-2 -yl] piperazine-1-carboxylate, at 0 ° C, and the resulting mixture was stirred at room temperature for 4 hours. 0.187 g of mercury (II) acetate and 0.090 g of sodium borohydride were added to the solution, and the resulting mixture was stirred at room temperature for 15 hours. 100 ml of ethyl acetate and 50 ml of 0.5N are added to the solution. hydrochloric acid and the organic layer are washed successively with 50 ml of water and 50 ml of a saturated solution of sodium chloride. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 0.172 g of the starting material was contained in the fraction eluted with hexane-ethyl acetate (4: 1). Thus, from the fraction eluted with hexane-ethyl acetate (1: 4), 0.061 g of the title compound was obtained.

¹ H-NMR (CDCl ₃ )

δ 1.42 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 1.81 (t, J = 2.3 Hz, 3H), 3.17-3.21 ( m, 4H), 3.41 (t, J = 4.8 Hz, 1H), 3.56-3.60 (m, 4H), 4.36 (q, J = 7.1 Hz, 2H), 4.75 (d, J = 4.8 Hz, 2H); 4.81 (q, J = 2.3 Hz, 2H).

(g) tert-Butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl] piperazine-1-carboxylate

0.120 g of manganese dioxide is added to a solution of 0.061 g of tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-hydroxymethyl-1H-imidazol-2-yl] piperazine-1-carboxylate in 2 ml of dichloromethane and the resulting mixture was stirred at room temperature for 15 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, from the fraction eluted with hexane-ethyl acetate (7: 3), 0.055 g of the title compound is obtained.

¹ H-NMR (CDCl ₃ )

δ 1.42 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 1.82 (t, J = 2.3 Hz, 3H), 3.23-3.26 ( m, 4H), 3.55-3.59 (m, 4H), 4.45 (q, J = 7.1 Hz, 2H), 4.89 (q, J = 2.3 Hz, 2H), 10.36 (s, 1H).

(h) tert-Butyl-4- [1- (2-butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin- 1-carboxylate

0.05 ml of methylhydrazine was added to a solution of 0.055 g of tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl] piperazine-1-carboxylate in 2.5 ml of ethanol. The mixture is stirred at 80 ° C for 15 hours and then heated at 130 ° C for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, from the fraction eluted with hexane-ethyl acetate (1: 1), 0.035 g of the title compound is obtained.

¹ H-NMR (CDCl ₃ )

δ 1.52 (s, 9H), 1.83 (t, J = 2.3 Hz, 3H), 3.38-3.42 (m, 4H), 3.61-3.64 (m, 4H ), 3.85 (s, 3H), 5.09 (q, J = 2.3 Hz, 2H), 8.13 (s, 1H).

MS m / e (ESI) 387.4 (MH ⁺ ).

(i) 3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

0.4 ml of trifluoroacetic acid is added to 0.4 ml of a solution of 0.0351 g of tert-butyl-4- [1- (2-butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [ 4,5-d] pyridazin-2-yl] piperazin-1-carboxylate in dichloromethane and the resulting mixture was stirred at room temperature for one hour. The solution is concentrated. The residue was purified by reversed-phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.0295 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.83 (t, J = 2.3 Hz, 3H), 3.45-3.49 (m, 4H), 3.65-3.69 (m, 4H), 3.83 (s, 3H ), 5.15 (q, J = 2.3 Hz, 2H), 8.20 (s, 1H).

MS m / e (ESI) 287.9 (MH ⁺ -CF ₃ COOH).

Example 116

5-Benzyloxymethyl-3- (2-butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) 5-Benzyloxymethyl-4-oxo-4,5-dihydroimidazo [4,5-d] pyridazin-1-sulfonic acid dimethylamide

2.08 g of triethylamine, 2.80 g of N, N-dimethylsulfamoyl chloride and 0.22 g of 4-dimethylaminopyridine are added to 50 ml of a dichloromethane solution containing 3.04 g of 5-benzyloxymethylimidazo [4,5-d] pyridazin-4-one [CAS No. 82137-50-6] (R. Paul Gagnier, Michael J. Halat, Brian A. Otter Journal of Heterocyclic Chemistry, 21, p. 481, 1984), and the resulting mixture was heated under reflux for 4 hours. 250 ml of ethyl acetate was added to the solution, and the mixture was washed successively with 50 ml of 1N. an aqueous solution of hydrochloric acid, 50 ml of a saturated solution of sodium bicarbonate and 50 ml of a saturated solution of sodium chloride. The resulting mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.86 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (2: 3).

¹ H-NMR (CDCl ₃ )

δ 2.98 (s, 6H), 4.77 (s, 2H), 5.74 (s, 2H), 7.30-7.39 (m, 5H), 8.21 (s, 1H), 8.46 (s, 1H).

(b) 5-Benzyloxymethyl-2-chloro-4-oxo-4,5-dihydroimidazo [4,5-d] pyridazine-1-sulfonic acid dimethylamide

5.3 ml of n-butyl lithium (2.0 M cyclohexane solution) in nitrogen atmosphere is added at -78 ° C in 150 ml of a tetrahydrofuran solution containing 3.34 g of 5-benzyloxymethyl-4-oxo-4,5-dihydroimidazo dimethylamide [4, 5-d] pyridazine-1-sulfonic acid and the resulting mixture was stirred at -78 ° C for one hour. To the resulting solution was added 20 ml of a solution of 3.26 g of hexachloroethane in tetrahydrofuran. The mixture was allowed to warm to room temperature. To the resulting solution was added 25 ml of a 5% aqueous solution of ammonium chloride, the mixture was extracted with 50 ml of ethyl acetate. The organic layer was washed successively with 25 ml of water and 25 ml of a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The organic phase is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. Thus, 2.31 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (2: 3).

¹ H-NMR (CDCl ₃ )

δ 3.12 (s, 6H), 4.77 (s, 2H), 5.70 (s, 2H), 7.30-7.39 (m, 5H), 8.48 (s, 1H).

(c) tert-Butyl-4- (6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazine-1-carboxylate

A mixture consisting of 2.31 g of 5-benzyloxymethyl-2-chloro-4-oxo-4,5-dihydroimidazo [4,5-d] pyridazine-1-sulfonic acid dimethylamide and 4.49 g of tert-butylpiperazine-1-carboxylate , heated at 150 ° C in nitrogen atmosphere for 2.5 hours. The resulting residue was purified by silica gel column chromatography. Thus, 1.94 g of the title compound is obtained from the fraction eluted with ethyl acetate.

¹ H-NMR (CDCl ₃ )

δ 3.54-3.58 (m, 4H), 3.71-3.75 (m, 4H), 4.68 (s, 2H), 5.65 (s, 2H), 7.25-7 35 (m, 5H), 8.21 (s, 1H), 12.58 (br s, 1H).

(d) tert-Butyl-4- [6-benzyloxymethyl-1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin- 1-carboxylate

0.74 g of potassium carbonate and 0.078 g of 2-butynyl bromide are added to 20 ml of a solution of 0.216 g of tert-butyl-4- (6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazin-1-carboxylate in N, N-dimethylformamide and the resulting mixture was stirred at room temperature for 16 hours. Then, 50 ml of ethyl acetate was added to the solution. The organic layer is washed three times with 20 ml of water and then with 10 ml of a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.139 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3: 2).

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.86 (t, J = 2.3 Hz, 3H), 3.38-3.44 (m, 4H), 3.61-3.66 (m, 4H ), 4.72 (s, 2H), 5.10 (q, J = 2.3 Hz, 2H), 5.65 (s, 2H), 7.25-7.38 (m, 5H), 8 , 18 (s, 1H).

(e) 5-Benzyloxymethyl-3- (2-butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

0.0043 g of the title compound was obtained by treating 0.0073 g of tert-butyl-4- [6-benzyloxymethyl-1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5 -d] pyridazin-2-yl] piperazine-1-carboxylate and purification of the obtained product according to the method of example 115 (i).

¹ H-NMR (CD ₃ OD)

δ 1.83 (t, J = 2.3 Hz, 2H), 3.45-3.49 (m, 4H), 3.65-3.69 (m, 4H), 4.69 (s, 2H) ), 5.15 (q, J = 2.3 Hz, 2H), 5.64 (s, 2H), 7.17-7.32 (m, 5H), 8.20 (s, 1H).

Mass spectrum m / e (ESI) 393.28 (MH ⁺ —CF ₃ COOH).

Example 117

3- (2-Butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

8 ml of a dichloromethane solution containing 0.123 g of tert-butyl-4- [6-benzyloxymethyl-1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2 -yl] piperazine-1-carboxylate, cooled to -78 ° C under nitrogen atmosphere, and 1.9 ml of boron trichloride (1.0 M solution in dichloromethane) was added to the mixture. The mixture was stirred at -78 ° C for five hours and 10 ml of a mixture of dichloromethane and methanol was added in a 1: 1 ratio. The resulting mixture was stirred at -78 ° C for two hours and then allowed to warm to room temperature. The solvent was removed under reduced pressure, and 10 ml of methanol was added to the mixture. Then, the solution was again concentrated under reduced pressure. The residue was dissolved in 3 ml of pyridine and the resulting mixture was heated under reflux for two hours. 0.3 ml of such a solution was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.005 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.83 (t, J = 2.3 Hz, 3H), 3.45-3.49 (m, 4H), 3.65-3.69 (m, 4H), 5.16 (q, J = 2.3 Hz, 2H); 8.21 (s, 1H).

Mass spectrum m / e (ESI) 273.16 (MH ⁺ —CF ₃ COOH).

Example 118

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide hydrochloride

(a) tert-Butyl-4- [7- (2-butynyl) -2- (2-carbamoylphenoxy) -1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine- 1-carboxylate

200 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 2.0 ml of 1-methyl-2-pyrrolidone and 85 mg of salicylamide and 129 mg of potassium carbonate are added. The resulting mixture was stirred at 100 ° C for 2 hours. After the reaction mixture was cooled to room temperature, 5.0 ml of water was added. After stirring at room temperature for 1 hour, the resulting white precipitate was collected by filtration. The resulting white solid was washed with water and ether to give 221 mg of the title compound (89%).

¹ H-NMR (DMSO-d ₆ )

δ 1.43 (s, 9H), 1.79 (t, J = 2.5 Hz, 3H), 3.23-3.27 (m, 4H), 3.36 (s, 3H), 3, 48-3.52 (m, 4H), 4.95 (q, 2.5 Hz, 2H), 6.59 (td, J = 8.0, 1.0 Hz, 1H), 6.63 (dd , J = 8.0, 1.0 Hz, 1H), 7.14 (ddd, J = 8.0, 7.5, 2.0 Hz, 1H), 7.80 (dd, J = 7.5 , 2.0 Hz, 1H).

MS m / e (ESI) 522 (MH ⁺ ).

(b) 2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide hydrochloride

210 mg tert-butyl-4- [7- (2-butynyl) -2- (2-carbamoylphenoxy) -1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazin-1 -carboxylate combined with 3.5 ml of methanol and 2.1 ml of a mixture of 4 N. hydrochloric acid with ethyl acetate. After the mixture was stirred at room temperature for 4 hours, the reaction solution was concentrated by purging with nitrogen gas. The resulting precipitate was washed with ethanol and ethyl acetate to obtain 177 mg of the title compound (96%).

¹ H-NMR (DMSO-d ₆ )

δ 1.82 (t, J = 2.3 Hz, 3H), 3.28-3.32 (m, 4H), 3.48 (s, 3H), 3.54-3.58 (m, 4H ), 5.04 (br, 2.3 Hz, 2H), 6.96 (br, J = 7.0 Hz, 1H), 6.99 (br, J, 8.0 Hz, 1H ), 7.46 (ddd, J = 8.0, 7.0, 1.5 Hz, 1H), 7.93 (brd, J = 8.0 Hz, 1H).

MS m / e (ESI) 422 (MH ⁺ -HCl).

Example 119

3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one

(a) 5-Methyl-1-trityl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one

78.8 g of 5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one [CAS No. 76756-58-6] (Shih-Fong Chen and Raymond P. Panzica, Journal of Organic Chemistry 46, p. 2467, 1981) are suspended in 2.5 L of dichloromethane at room temperature and 78.8 g of triethylamine are added to the mixture. 176 g of trityl chloride are added and the resulting mixture is stirred for three hours. 7.5 L of ethyl acetate was added to the mixture. After washing successively with 3 L of water and 3 L of a saturated solution of sodium chloride, the mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 136.5 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (20:80 - 0: 100).

¹ H-NMR (CDCl ₃ )

δ 3.79 (s, 3H), 6.92 (s, 1H), 7.07-7.13 (m, 6H), 7.32-7.40 (m, 9H), 7.87 (s , 1H).

(b) 2-Chloro-5-methyl-1-trityl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one

220 ml of lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran) in a nitrogen atmosphere at -75 ° C is added to 4 l of a tetrahydrofuran solution containing 68.3 g of 5-methyl-1-trityl-1,5-dihydroimidazo [4,5-d ] pyridazin-4-one, and the resulting mixture was stirred at -75 ° C for 1 hour. Then, 200 ml of a tetrahydrofuran solution containing 82.3 g of hexachloroethane are added to the resulting solution. The mixture is allowed to warm to -20ºС. 5 L of a 5% aqueous solution of ammonium chloride was added and the mixture was extracted with 4 L of ethyl acetate. The organic layer was washed successively with 5 L of water and 5 L of a saturated solution of sodium chloride. The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was suspended in 150 ml of tert-butyl methyl ether and then filtered. The resulting solid was washed twice with 100 ml of tert-butyl methyl ether to give 69.7 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 3.78 (s, 3H), 5.81 (s, 1H), 7.25-7.27 (m, 6H), 7.28-7.38 (m, 9H).

(c) tert-Butyl-4- (6-methyl-7-oxo-6,7-dihydro-1H-imidazole [4,5-d] pyridazin-2-yl) piperazine-1-carboxylate

69.7 g of 2-chloro-5-methyl-1-trityl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one is combined with 153.4 g of tert-butylpiperazine-1-carboxylate and the resulting mixture is stirred and heated to 100 ° C in a nitrogen atmosphere. After the mixture becomes easily mixed, the temperature is increased to 150 ° C. The mixture is kept at this temperature for 1 hour. The reaction solution was allowed to cool and then suspended in 250 ml of tert-butyl methyl ether. Suspended material is collected by filtration. The solid is washed twice with 200 ml of tert-butyl methyl ether and three times with 200 ml of water. The resulting solid was again washed twice with 200 ml of tert-butyl methyl ether and dried to give 50.3 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 3.56-3.62 (m, 4H), 3.73-3.80 (m, 4H), 3.87 (s, 3H), 8.16 (s , 1H); 12.65 (br s, 1H).

(d) tert-Butyl-4- [1- (2-butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin- 1-carboxylate

43.9 g of potassium carbonate and 27.8 ml of 2-butynyl bromide, at 15 ° C under nitrogen atmosphere, are successively added to 5.5 l of a solution of 88.4 g of tert-butyl-4- (6-methyl-7-oxo-6, 7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazine-1-carboxylate in N, N-dimethylformamide. The reaction solution was stirred at room temperature for 22 hours and then poured into 10 L of water. The mixture was extracted with 5 L of ethyl acetate. The organic layer is washed twice with 5 L of water and 5 L of a saturated solution of sodium chloride. The aqueous layer was extracted twice with 3 L of ethyl acetate. The organic layers are combined and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 54.3 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3: 2 - 3: 7).

¹ H-NMR (CDCl ₃ )

δ 1.52 (s, 9H), 1.83 (t, J = 2.3 Hz, 3H), 3.38-3.42 (m, 4H), 3.61-3.64 (m, 4H ), 3.85 (s, 3H), 5.09 (q, J = 2.3 Hz, 2H), 8.13 (s, 1H).

(e) 3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one

200 ml of trifluoroacetic acid is added to 200 ml of a dichloromethane solution containing 54.3 g of tert-butyl-4- [1- (2-butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4 , 5-d] pyridazin-2-yl] piperazine-1-carboxylate, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in 500 ml of ethyl acetate. Gradually add 1 liter of a 10% aqueous sodium bicarbonate solution. After that, 1 l of ethyl acetate and 500 ml of 5 N are added to the solution. an aqueous solution of sodium hydroxide. The resulting organic layer was separated. The aqueous layer was extracted five times with 1 L of dichloromethane. The organic layers are combined, washed with 500 ml of 2 N. an aqueous solution of sodium hydroxide, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 30.5 g of the title compound as crystals.

¹ H-NMR (CDCl ₃ )

δ 1.84 (t, J = 2.3 Hz, 3H), 3.05-3.09 (m, 4H), 3.38-3.44 (m, 4H), 3.85 (s, 3H ), 5.06 (q, J = 2.3 Hz, 2H), 8.13 (s, 3H).

Example 119-2

3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one toluene-4-sulfonate

98.7 mg of 3- (2-butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one is dissolved in ethanol and then with stirring add 1 ml of an ethanol solution containing 101 mg of p-toluenesulfonic acid monohydrate. The mixture is cooled with ice for two hours with stirring. The resulting precipitate was collected by filtration and then dried at 50 ° C under reduced pressure for one hour to obtain 153.2 mg of the title compound.

¹ H-NMR (DMSO-d ₆ )

δ 1.79 (t, J = 2 Hz, 3H), 2.27 (s, 3H), 3.25-3.35 (m, 4H), 3.50-3.54 (m, 4H), 3.70 (s, 3H), 5.13 (d, J = 2 Hz, 2H), 7.10 (d, J = 8 Hz, 2H), 7.47 (d, J = 8 Hz, 2H) 8.25 (s, 1H); 8.79 (br s, 2H).

In addition, 107.95 mg of the title compound was recrystallized from acetone to give 84.9 mg of a crystalline product.

Example 120

2- (3-aminopiperidin-1-yl) -3- (2-butynyl) -5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) 9H-Fluoren-9-ylmethyl-3-tert-butoxycarbonylaminopiperidine-1-carboxylate

1.84 g of diisopropylethylamine and 4.71 g of diphenylphosphorylazide are added to 10 ml of a solution of 5.01 g of 9H-fluoren-9-ylmethyl 3-carboxypiperidin-1-carboxylate in tert-butanol and the resulting mixture is heated at 60 ° C for 18 hours in the atmosphere nitrogen. The reaction solution was cooled and 150 ml of ethyl acetate was added. The organic layer is washed successively with 100 ml of a 5% aqueous solution of sulfuric acid, 100 ml of a 5% aqueous solution of sodium bicarbonate, 100 ml of water and 100 ml of a saturated solution of sodium chloride, then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Thus, 1.88 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (4: 1).

¹ H-NMR (CDCl ₃ )

δ 1.45 (s, 9H), 1.45-1.72 (m, 3H), 1.82-1.87 (br s, 1H), 3.09-3.30 (br s, 2H), 3.58 (br.s, 2H), 3.82-3.98 (br.s, 1H), 4.24 (t, J = 7.2 Hz, 1H), 4.27-4 48 (br.s, 2H), 4.52-4.59 (br.s, 1H), 7.32 (dd, J = 10.3, 10.0 Hz, 2H), 7.39 (t , J = 10.0 Hz, 2H), 7.59 (d, J = 10.0 Hz, 2H), 7.75 (d, J = 10.3 Hz, 2H).

(b) tert-butylpiperdin-3-ylcarbamate

25 ml of diethylamine are added to 250 ml of an ethanol solution of 1.88 g of 3-tert-butoxycarbonylaminopiperidine-1-carboxylate, and the resulting mixture is stirred at room temperature for 18 hours. After the solution was concentrated under reduced pressure, the residue was dissolved in a mixture of 150 ml of toluene and 100 ml of a 10% aqueous citric acid solution. The aqueous layer is alkalinized 5 N. aqueous sodium hydroxide solution and then extracted twice with 100 ml of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.79 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.45 (s, 9H), 1.41-1.53 (m, 2H), 1.65-1.72 (m, 1H), 1.79-1.86 (m, 1H), 2 , 48-2.56 (m, 1H), 2.64-2.70 (m, 1H), 2.78-2.86 (m, 1H), 3.06 (dd, J = 12.0, 4.0 Hz, 1H), 3.48-3.62 (br s, 1H), 4.71-4.88 (br s, 1H).

c) 2- (3-Aminopiperidin-1-yl) -3- (2-butynyl) -5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

0.020 g of 2-chloro-5-methyl-1-trityl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one and 0.040 g of tert-butylpiperidin-3-ylcarbamate are mixed with each other and the resulting mixture is heated at 150ºС for 1 hour in a nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography. From the fraction eluted with ethyl acetate, 0.016 g of tert-butyl [1- (6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperidin-3- is obtained silt] carbamate. 0.0080 g of the obtained compound was dissolved in 0.6 ml of N, N-dimethylformamide, and then 0.0038 g of potassium carbonate and 0.003 ml of 2-butynyl bromide were added to the solution. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between 1 ml of ethyl acetate and 1 ml of water, and the organic layer was concentrated. The residue was dissolved in 0.5 ml of dichloromethane and then 0.5 ml of trifluoroacetic acid was added. After one hour, the reaction solution was concentrated. The resulting residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 0.0046 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.74-1.80 (br.s, 1H), 1.82 (br.s, 3H), 1.96-2.19 (br.m, 3H), 3.43-3.79 ( br.m, 5H), 3.86 (s, 3H), 5.05 (br.s, J = 16.0 Hz, 1H), 5.23 (br.s, J = 16.0 Hz, 1H ), 8.15 (s, 1H).

Example 121

2- (3-aminopiperidin-1-yl) -5-methyl-3- (3-methyl-2-butenyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

0.0034 g of the title compound was prepared using 0.0080 g of tert-butyl- [1- (6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2 -yl) piperidin-3-yl] carbamate and 0.004 ml of 4-bromo-2-methyl-2-butene, following the method described in example 120.

¹ H-NMR (CDCl ₃ )

δ 1.66-1.74 (br s, 1H), 1.76 (s, 3H), 1.80 (s, 3H), 1.96-2.20 (br.m, 3H), 3 , 20-3.79 (br.m, 5H), 3.85 (s, 3H), 4.90-5.05 (m, 2H), 5.37-5.42 (m, 1H), 8 15 (s, 1H).

Example 122

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide

53.0 g of tert-butyl-4- [7- (2-butynyl) -2- (2-carbamoylphenoxy) -1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine -1-carboxylate is dissolved in 160 ml of trifluoroacetic acid and the resulting mixture is stirred at room temperature for one hour. 1250 ml of a 2 M aqueous sodium hydroxide solution was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 1 hour 50 minutes. The resulting white precipitate was collected by filtration. The white solid was washed with water and then ethanol, dried overnight at 60 ° C, whereby 42.8 g of the title compound was obtained.

¹ H-NMR (DMSO-d ₆ )

δ 1.78 (t, J = 2.4 Hz, 3H), 2.82-2.86 (m, 4H), 3.18-3.22 (m, 4H), 3.36 (s, 3H ), 4.91 (q, 2.4 Hz, 2H), 6.58 (td, J = 8.4, 1.2 Hz, 1H), 6.63 (dd, J = 8.0, 0, 8 Hz, 1H), 7.14 (ddd, J = 8.0, 7.2, 2.0 Hz, 1H), 7.80 (dd, J = 7.6, 2.0 Hz, 1H).

MS m / e (ESI) 422 (MH ⁺ ).

Example 123

7- (2-Butynyl) -2- (3-hydroxypropylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

7 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, then 20 μl of 3-mercapto-1-propanol and 6 mg of potassium carbonate are added. The resulting mixture was stirred at room temperature for five hours. A saturated solution of ammonium chloride was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and 0.5 ml of 5 N was added to the residue. aqueous hydrochloric acid. The mixture was concentrated by purging with nitrogen gas. The resulting residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 3.15 mg of the title compound.

MS m / e (ESI) 377 (MH ⁺ -CF ₃ COOH).

Example 124

7- (2-Butynyl) -2- (2-hydroxypropylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

1.70 mg of the title compound was obtained by the method of Example 123 using 1-mercapto-2-propanol instead of 3-mercapto-1-propanol.

MS m / e (ESI) 377 (MH ⁺ -CF ₃ COOH).

Example 125

7- (2-Butynyl) -2- (2,3-dihydroxypropylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

2.63 mg of the title compound was obtained by the method of Example 123 using 3-mercapto-1,2-propanediol instead of 3-mercapto-1-propanol.

MS m / e (ESI) 393 (MH ⁺ -CF ₃ COOH).

Example 126

3- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] propionic acid trifluoroacetate

7 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, then 20 μl of 3-mercaptopropionic acid and 6 mg of potassium carbonate are added. The mixture was stirred at room temperature for five hours. A saturated solution of ammonium chloride was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 0.40 ml of trifluoroacetic acid. The solution was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 4.60 mg of the title compound.

MS m / e (ESI) 391 (MH ⁺ -CF ₃ COOH).

Example 127

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] propionic acid trifluoroacetate

6.10 mg of the title compound was prepared according to the method of Example 126 using 2-mercaptopropionic acid instead of 3-mercaptopropionic acid.

MS m / e (ESI) 391 (MH ⁺ -CF ₃ COOH).

Example 128

2-sec-butylsulfanyl-7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

4.68 mg of the title compound was prepared according to the method of Example 126 using butan-2-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 375 (MH ⁺ -CF ₃ COOH).

Example 129

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2-propylsulfanyl-1,7-dihydropurin-6-one trifluoroacetate

4.61 mg of the title compound was obtained by the method of Example 126 using propan-1-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 361 (MH ⁺ -CF ₃ COOH).

Example 130

7- (2-Butynyl) -1-methyl-2-cyclopentylsulfanyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

5.15 mg of the title compound was obtained by the method of Example 126 using cyclopentantiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 387 (MH ⁺ -CF ₃ COOH).

Example 131

7- (2-Butynyl) -2-dodecylsulfanyl-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

4.96 mg of the title compound was prepared according to the method of Example 126 using dodecan-1-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 487 (MH ⁺ -CF ₃ COOH).

Example 132

2- (2-Aminoethylsulfanyl) -7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

3.98 mg of the title compound was prepared according to the method of Example 126 using 2-aminoethanethiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 362 (MH ⁺ -CF ₃ COOH).

Example 133

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (thiophen-2-ylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate

5.11 mg of the title compound was obtained by the method of Example 126 using thiophene-2-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 401 (MH ⁺ -CF ₃ COOH).

Example 134

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (1H- [1,2,4] triazol-3-ylsulfanyl) -1,7-dihydropurin-6- trifluoroacetate she

2.54 mg of the title compound was prepared according to the method of Example 126, using 1H- [1,2,4] triazole-3-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 386 (MH ⁺ -CF ₃ COOH).

Example 135

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (pyridin-4-ylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate

0.77 mg of the title compound was prepared according to the method of Example 126 using pyridin-4-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 396 (MH ⁺ -CF ₃ COOH).

Example 136

7- (2-Butynyl) -1-methyl-2-phenylsulfanyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

1.44 mg of the title compound was prepared according to the method of Example 126, using benzenethiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 395 (MH ⁺ -CF ₃ COOH).

Example 137

(R) -2-amino-3- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2- trifluoroacetate ilsulfanyl] propionic acid

4.38 mg of the title compound was prepared according to the method of Example 126 using L-cystine instead of 3-mercaptopropionic acid.

MS m / e (ESI) 406 (MH ⁺ -CF ₃ COOH).

Example 138

7- (2-Butynyl) -2- (2-methylpropylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

4.52 mg of the title compound was obtained by the method of Example 126 using 2-methylpropan-1-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 375 (MH ⁺ -CF ₃ COOH).

Example 139

7- (2-Butynyl) -2- (1,2-dimethylpropylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

3.03 mg of the title compound was obtained by the method of Example 126 using 2-methylbutan-1-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 389 (MH ⁺ -CF ₃ COOH).

Example 140

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (pyrimidin-2-ylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate

3.60 mg of the title compound was obtained by the method of Example 126 using pyrimidin-2-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 397 (MH ⁺ -CF ₃ COOH).

Example 141

7- (2-Butynyl) -2- (1H-imidazol-2-ylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

5.75 mg of the title compound was obtained according to the method of Example 126, using 1H-imidazole-2-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 385 (MH ⁺ -CF ₃ COOH).

Example 142

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (thiazol-2-ylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate

3.86 mg of the title compound was prepared according to the method of Example 126, using thiazole-2-thiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 402 (MH ⁺ -CF ₃ COOH).

Example 143

7- (2-Butynyl) -2- (furan-2-ylmethylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

4.84 mg of the title compound was obtained by the method of Example 126 using (furan-2-yl) methanethiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 399 (MH ⁺ -CF ₃ COOH).

Example 144

Trifluoroacetate 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] acetamide

1.86 mg of the title compound was prepared according to the method of Example 126 using 2-mercaptoacetamide instead of 3-mercaptopropionic acid.

MS m / e (ESI) 376 (MH ⁺ -CF ₃ COOH).

Example 145

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (thiophen-2-ylmethylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate

3.35 mg of the title compound was prepared according to the method of Example 126 using (thiophen-2-yl) methanethiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 415 (MH ⁺ -CF ₃ COOH).

Example 146

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- [1- (thiophen-2-yl) ethylsulfanyl] -1,7-dihydropurin-6-one trifluoroacetate

0.51 mg of the title compound was prepared according to the method of Example 126 using 1- (thiophen-2-yl) ethanethiol instead of 3-mercaptopropionic acid.

MS m / e (ESI) 429 (MH ⁺ -CF ₃ COOH).

Example 147

7- (2-Butynyl) -1-methyl-2- (1-methyl-1H-imidazol-2-ylsulfanyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

5 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, then 10 mg of 1-methyl-1H-imidazole-2-thiol and 8 mg of potassium carbonate are added. The mixture was stirred at room temperature for five hours. A saturated solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 0.40 ml of trifluoroacetic acid. The solution was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 3.75 mg of the title compound.

MS m / e (ESI) 399 (MH ⁺ -CF ₃ COOH).

Example 148

7- (2-Butynyl) -1-methyl-2- (4-methylpyrimidin-2-ylsulfanyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

4.00 mg of the title compound was obtained by the method of Example 147 using 4-methylpyrimidin-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 411 (MH ⁺ -CF ₃ COOH).

Example 149

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (pyrazin-2-ylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate

4.00 mg of the title compound was obtained according to the method of Example 147 using pyrazin-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 411 (MH ⁺ -CF ₃ COOH).

Example 150

Trifluoroacetate 2- (Benzothiazol-2-ylsulfanyl) -7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one

0.07 mg of the title compound was prepared according to the method of Example 147 using benzothiazole-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 452 (MH ⁺ -CF ₃ COOH).

Example 151

2- (1H-Benzimidazol-2-ylsulfanyl) -7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

3.18 mg of the title compound was prepared according to the method of Example 147 using 1H-benzimidazole-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 435 (MH ⁺ -CF ₃ COOH).

Example 152

Trifluoroacetate 2- (5-amino [1,3,4] thiadiazol-2-ylsulfanyl) -7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6 -she

3.62 mg of the title compound was prepared according to the method of Example 147 using 5-amino [1,3,4] thiadiazole-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 418 (MH ⁺ -CF ₃ COOH).

Example 153

6- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] nicotinic trifluoroacetate

1.01 mg of the title compound was obtained by the method of Example 147 using 6-mercaptonicotinic acid instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 440 (MH ⁺ -CF ₃ COOH).

Example 154

7- (2-Butynyl) -2- (4-methoxyphenylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

4.14 mg of the title compound was prepared according to the method of Example 147 using 4-methoxybenzenethiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 425 (MH ⁺ -CF ₃ COOH).

Example 155

7- (2-Butynyl) -1-methyl-2- (4-nitrophenylsulfanyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

1.52 mg of the title compound was prepared according to the method of Example 147 using 4-nitrobenzenethiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 440 (MH ⁺ -CF ₃ COOH).

Example 156

N- [2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] ethyl] acetamide trifluoroacetate

2.39 mg of the title compound was obtained by the method of Example 147 using N- (2-mercaptoethyl) acetamide instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 404 (MH ⁺ -CF ₃ COOH).

Example 157

Trifluoroacetate 7- (2-butynyl) -1-methyl-2- (5-methyl [1,3,4] thiadiazol-2-ylsulfanyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6 -she

1.24 mg of the title compound was prepared according to the method of Example 147 using 5-methyl [1,3,4] thiadiazole-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 417 (MH ⁺ -CF ₃ COOH).

Example 158

7- (2-Butynyl) -2- (4,6-dimethylpyrimidin-2-ylsulfanyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

3.11 mg of the title compound was obtained by the method of Example 147 using 4,6-dimethylpyrimidin-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 425 (MH ⁺ -CF ₃ COOH).

Example 159

7- (2-Butynyl) -1-methyl-2- (4-methylthiazol-2-ylsulfanyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

4.01 mg of the title compound was prepared according to the method of Example 147, using 4-methylthiazole-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 416 (MH ⁺ -CF ₃ COOH).

Example 160

2- (Benzoxazol-2-ylsulfanyl) -7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

0.84 mg of the title compound was prepared according to the method of Example 147 using benzoxazole-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 436 (MH ⁺ -CF ₃ COOH).

Example 161

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2 - ([1,3,4] thiadiazol-2-ylsulfanyl) -1,7-dihydropurin-6-one trifluoroacetate

1.95 mg of the title compound was prepared according to the method of Example 147 using [1,3,4] thiadiazole-2-thiol instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 403 (MH ⁺ -CF ₃ COOH).

Example 162

2-Allylsulfanyl-7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

2.85 mg of the title compound was prepared according to the method of Example 147 using allyl mercaptan instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 359 (MH ⁺ -CF ₃ COOH).

Example 163

7- (2-Butynyl) -1-methyl-2- (3-methylsulfanylphenylamino) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

1.32 mg of the title compound was prepared according to the method of Example 147 using 3-methylsulfanylphenylamine instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 424 (MH ⁺ -CF ₃ COOH).

Example 164

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (thiomorpholin-4-yl) -1,7-dihydropurin-6-one trifluoroacetate

5.33 mg of the title compound was prepared according to the method of Example 147 using thiomorpholine instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 388 (MH ⁺ -CF ₃ COOH).

Example 165

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] -2-methylpropionic acid trifluoroacetate

1.63 mg of the title compound was obtained by the method of Example 147 using 2-mercapto-2-methylpropionic acid instead of 1-methyl-1H-imidazole-2-thiol.

MS m / e (ESI) 405 (MH ⁺ -CF ₃ COOH).

Example 166

7- (2-Butynyl) -2- (N-isopropylmethylamino) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and then 30 μl of N-isopropylmethylamine are added to the solution. After the mixture was stirred at 80 ° C for 12 hours, the reaction solution was concentrated by purging with nitrogen gas. The resulting residue was dissolved in 0.60 ml of trifluoroacetic acid. The solution was concentrated by purging with nitrogen gas. The resulting residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 1.66 mg of the title compound.

MS m / e (ESI) 358 (MH ⁺ -CF ₃ COOH).

Example 167

3- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzonitrile trifluoroacetate

5 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of 1-methyl-2-pyrrolidone, then 5 mg of 3-cyanophenol and 8 mg of sodium hydride are added. The mixture is stirred at 90 ° C for three hours. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.02 mg of the title compound.

MS m / e (ESI) 404 (MH ⁺ -CF ₃ COOH).

Example 168

4- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzonitrile trifluoroacetate

2.76 mg of the title compound was prepared according to the method of Example 167 using 4-cyanophenol instead of 3-cyanophenol.

MS m / e (ESI) 404 (MH ⁺ -CF ₃ COOH).

Example 169

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (3-tolyloxy) -1,7-dihydropurin-6-one trifluoroacetate

3.14 mg of the title compound was prepared according to the method of Example 167 using 3-methylphenol instead of 3-cyanophenol.

MS m / e (ESI) 393 (MH ⁺ -CF ₃ COOH).

Example 170

7- (2-Butynyl) -1-methyl-2- (2-methylsulfanylphenoxy) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

3.50 mg of the title compound was prepared according to the method of Example 167 using 2-methylsulfanylphenol instead of 3-cyanophenol.

MS m / e (ESI) 425 (MH ⁺ -CF ₃ COOH).

Example 171

3- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzoic acid trifluoroacetate

5 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate and 10 mg of ethyl 3-hydroxybenzoate was dissolved in 0.2 ml of N-methylpyrrolidone and 8 mg of sodium hydride was added to the mixture. The resulting mixture was stirred at 90 ° C for 3 hours. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in a mixture of 0.4 ml of ethanol and 0.1 ml of 5 N. an aqueous solution of sodium hydroxide. The resulting mixture was stirred at 50 ° C. overnight. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The resulting solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.09 mg of the title compound.

MS m / e (ESI) 423 (MH ⁺ -CF ₃ COOH).

Example 172

4- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzoic acid trifluoroacetate

1.55 mg of the title compound was prepared according to the method of Example 171 using ethyl 4-hydroxybenzoate instead of 3-hydroxybenzoic acid.

MS m / e (ESI) 423 (MH ⁺ -CF ₃ COOH).

Example 173

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (2-tolyloxy) -1,7-dihydropurin-6-one trifluoroacetate

7 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of 1-methyl-2-pyrrolidone, then 5 mg of 2-methylphenol and 8 mg of potassium carbonate are added. The mixture is stirred at 90 ° C for five hours. To the reaction solution was added 1N. hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.40 mg of the title compound.

MS m / e (ESI) 393 (MH ⁺ -CF ₃ COOH).

Example 174

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (4-tolyloxy) -1,7-dihydropurin-6-one trifluoroacetate

3.95 mg of the title compound was prepared according to the method of Example 173 using 4-methylphenol instead of 2-methylphenol.

MS m / e (ESI) 393 (MH ⁺ -CF ₃ COOH).

Example 175

7- (2-Butynyl) -2- (2-methoxyphenoxy) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

5.24 mg of the title compound was prepared according to the method of Example 173 using 2-methoxyphenol instead of 2-methylphenol.

MS m / e (ESI) 409 (MH ⁺ -CF ₃ COOH).

Example 176

7- (2-Butynyl) -2- (3-methoxyphenoxy) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

2.84 mg of the title compound was prepared according to the method of Example 173 using 3-methoxyphenol instead of 2-methylphenol.

MS m / e (ESI) 409 (MH ⁺ -CF ₃ COOH).

Example 177

7- (2-Butynyl) -2- (4-methoxyphenoxy) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

5.61 mg of the title compound was prepared according to the method of Example 173 using 4-methoxyphenol instead of 2-methylphenol.

MS m / e (ESI) 409 (MH ⁺ -CF ₃ COOH).

Example 178

4- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzenesulfonamide trifluoroacetate

4.21 mg of the title compound was prepared according to the method of Example 173 using 4-hydroxybenzenesulfonamide instead of 2-methylphenol.

MS m / e (ESI) 458 (MH ⁺ -CF ₃ COOH).

Example 179

4- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] -3-methoxybenzonitrile trifluoroacetate

4.24 mg of the title compound was prepared according to the method of Example 173 using 4-hydroxy-3-methoxybenzonitrile instead of 2-methylphenol.

MS m / e (ESI) 434 (MH ⁺ -CF ₃ COOH).

Example 180

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzonitrile trifluoroacetate

5.26 mg of the title compound was prepared according to the method of Example 173 using 2-cyanophenol instead of 2-methylphenol.

MS m / e (ESI) 404 (MH ⁺ -CF ₃ COOH).

Example 181

4- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide trifluoroacetate

4.80 mg of the title compound was prepared according to the method of Example 173 using 4-hydroxybenzamide instead of 2-methylphenol.

MS m / e (ESI) 422 (MH ⁺ -CF ₃ COOH).

Example 182

Ethyl 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzoate trifluoroacetate

4.38 mg of the title compound was prepared according to the method of Example 173 using ethyl 2-hydroxybenzoate instead of 2-methylphenol.

MS m / e (ESI) 451 (MH ⁺ -CF ₃ COOH).

Example 183

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (pyrimidin-2-yloxy) -1,7-dihydropurin-6-one trifluoroacetate

1.12 mg of the title compound was prepared according to the method of Example 173 using pyrimidin-2-ol instead of 2-methylphenol.

MS m / e (ESI) 381 (MH ⁺ -CF ₃ COOH).

Example 184

7- (2-Butynyl) -2- (4,6-dimethylpyrimidin-2-yloxy) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

0.66 mg of the title compound was obtained by the method of Example 173 using 4,6-dimethylpyrimidin-2-ol instead of 2-methylphenol.

MS m / e (ESI) 409 (MH ⁺ -CF ₃ COOH).

Example 185

3- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate and 10 mg of ethyl 3-hydroxybenzoate is dissolved in 0.2 ml of N-methylpyrrolidone, then 10 mg of potassium carbonate is added to the mixture. The mixture is stirred at 90 ° C for 3 hours. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 1.0 ml of ammonia (7 N methanol solution). The mixture was stirred at 50 ° C. overnight. The reaction solution was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.91 mg of the title compound.

MS m / e (ESI) 422 (MH ⁺ -CF ₃ COOH).

Example 186

4- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] -3,5-dimethylbenzoic trifluoroacetate acid

7 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of 1-methyl-2-pyrrolidone and 8 mg of 4-hydroxy-3,5-dimethylbenzoic acid and 8 mg of potassium carbonate are added to the resulting solution. The mixture is stirred at 100 ° C for 2 hours. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.71 mg of the title compound.

MS m / e (ESI) 451 (MH ⁺ -CF ₃ COOH).

Example 187

4- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] -3-fluorobenzoic acid trifluoroacetate

3.49 mg of the title compound was obtained by the method of Example 186 using 3-fluoro-4-hydroxybenzoic acid instead of 4-hydroxy-3,5-dimethylbenzoic acid.

MS m / e (ESI) 441 (MH ⁺ -CF ₃ COOH).

Example 188

[4- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] phenyl] acetate trifluoroacetate

3.45 mg of the title compound was prepared according to the method of Example 186 using (4-hydroxyphenyl) acetic acid instead of 4-hydroxy-3,5-dimethylbenzoic acid.

MS m / e (ESI) 437 (MH ⁺ -CF ₃ COOH).

Example 189

[2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] phenyl] acetic acid trifluoroacetate

1.34 mg of the title compound was prepared by the method of Example 186 using (2-hydroxyphenyl) acetic acid instead of 4-hydroxy-3,5-dimethylbenzoic acid.

MS m / e (ESI) 437 (MH ⁺ -CF ₃ COOH).

Example 190

2- (2-Acetylphenoxy) -7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

1.99 mg of the title compound was prepared according to the method of Example 186, using 1- (2-hydroxyphenyl) ethanone instead of 4-hydroxy-3,5-dimethylbenzoic acid.

MS m / e (ESI) 421 (MH ⁺ -CF ₃ COOH).

Example 191

7- (2-Butynyl) -2- (2,6-difluorophenoxy) -1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

5.26 mg of the title compound was prepared according to the method of Example 186 using 2,6-difluorophenol instead of 4-hydroxy-3,5-dimethylbenzoic acid.

MS m / e (ESI) 415 (MH ⁺ -CF ₃ COOH).

Example 192

7- (2-Butynyl) -1-methyl-2-pentafluorophenoxy-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

5.61 mg of the title compound was obtained by the method of Example 186 using 2,3,4,5,6-pentafluorophenol instead of 4-hydroxy-3,5-dimethylbenzoic acid.

MS m / e (ESI) 469 (MH ⁺ -CF ₃ COOH).

Example 193

7- (2-butynyl) -1-methyl-8- (piperazin-1-yl) -2- [4- (pyrrolidin-1-carbonyl) phenoxy] -1,7-dihydropurin-6-one trifluoroacetate

30 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 1 ml of 1-methyl-2-pyrrolidone, then 15 mg of 1- (4 hydroxybenzoyl) pyrrolidine and 11 mg of potassium carbonate are added to the solution. The mixture is stirred at 100 ° C for 2.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 23.7 mg of the title compound.

MS m / e (ESI) 476 (MH ⁺ -CF ₃ COOH).

Example 194

Trifluoroacetate 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] -N- [2- (piperidin-1-yl) ethyl] benzamide

3.05 mg of the title compound was prepared according to the method of Example 193 using 2-hydroxy-N- [2- (piperidin-1-yl) ethyl] benzamide.

MS m / e (ESI) 533 (MH ⁺ -CF ₃ COOH).

Example 195

5-Acetyl-2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide trifluoroacetate

0.82 mg of the title compound was prepared according to the method of Example 193 using 5-acetylsalicylamide instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 464 (MH ⁺ -CF ₃ COOH).

Example 196

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] benzoic acid trifluoroacetate

0.70 mg of the title compound was prepared according to the method of Example 193 using thiosalicylic acid instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 439 (MH ⁺ -CF ₃ COOH).

Example 197

6- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] nicotinamide trifluoroacetate

1.43 mg of the title compound was prepared according to the method of Example 193 using 6-aminonicotinamide instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 422 (MH ⁺ -CF ₃ COOH).

Example 198

3- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] pyridin-2-carboxylic amide trifluoroacetate acid

1.44 mg of the title compound was prepared according to the method of Example 193 using 3-hydroxypicolinamide instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 423 (MH ⁺ -CF ₃ COOH).

Example 199

N-tert-butyl-2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino trifluoroacetate] benzamide

0.87 mg of the title compound was prepared according to the method of Example 193 using 2-amino-N-tert-butylbenzamide instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 477 (MH ⁺ -CF ₃ COOH).

Examples 200 and 201

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] benzamide trifluoroacetate

1.36 mg of the polar derivative of the title compound and 0.39 mg of the non-polar derivative of the title compound were prepared according to the method of Example 193 using 2-aminobenzamide instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 477 (MH ⁺ -CF ₃ COOH).

Example 202

N- [3- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] phenyl] acetamide trifluoroacetate

10.79 mg of the title compound was prepared according to the method of Example 193 using 3-acetamidophenol instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 436 (MH ⁺ -CF ₃ COOH).

Example 203

N- [4- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] phenyl] acetamide trifluoroacetate

11.38 mg of the title compound was prepared according to the method of Example 193 using 4-acetamidophenol instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 436 (MH ⁺ -CF ₃ COOH).

Example 204

2- [N- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] methylamino] benzoic trifluoroacetate acid

3.48 mg of the title compound was prepared according to the method of Example 193 using 4-methylanthranilic acid instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 436 (MH ⁺ -CF ₃ COOH).

Example 205

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzoic acid trifluoroacetate

25.75 mg of the title compound was prepared according to the method of Example 193 using salicylic acid instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 423 (MH ⁺ -CF ₃ COOH).

Example 206

Trifluoroacetate 2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylamino] benzenesulfonamide

0.91 mg of the title compound was prepared according to the method of Example 193 using 2-aminobenzenesulfonamide instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 457 (MH ⁺ -CF ₃ COOH).

Example 207

2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-ylsulfanyl] benzoic acid ethyl ester trifluoroacetate

0.66 mg of the title compound was prepared according to the method of Example 193 using ethylthiosalicylate instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 467 (MH ⁺ -CF ₃ COOH).

Example 208

3- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] pyridine-2-carboxylic acid trifluoroacetate

4.36 mg of the title compound was prepared according to the method of Example 193 using 3-hydroxypicolinic acid instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 424 (MH ⁺ -CF ₃ COOH).

Example 209

N- [2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] phenyl] acetamide trifluoroacetate

0.126 mg of the title compound was prepared according to the method of Example 193 using 2-acetamidophenol instead of 1- (4-hydroxybenzoyl) pyrrolidine.

MS m / e (ESI) 436 (MH ⁺ -CF ₃ COOH).

Example 210

2- [7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] -N, N-dimethylbenzamide trifluoroacetate

100 mg of salicylic acid and 0.76 ml of a 2 M tetrahydrofuran solution of dimethylamine are dissolved in 1 ml of N, N-dimethylformamide, and 109 μl of diethyl cyanophosphate and 250 μl of triethylamine are added to the resulting solution. The mixture was stirred at room temperature for 5.5 hours. Water was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and 20 mg of 4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8 tert-butyl ester was added to one third of the aliquot of the residue. -yl] piperazine-1-carboxylic acid, potassium carbonate and 1 ml of 1-methyl-2-pyrrolidone. The mixture is stirred at 150 ° C for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.06 mg of the title compound.

MS m / e (ESI) 450 (MH ⁺ -CF ₃ COOH).

Example 211

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- [2- (thiazolidin-3-carbonyl) phenoxy] -1,7-dihydropurin-6-one trifluoroacetate

2.10 mg of the title compound was prepared according to the method of Example 210 using thiazolidine instead of dimethylamine.

MS m / e (ESI) 494 (MH ⁺ -CF ₃ COOH).

Example 212

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- [2- (pyrrolidin-1-carbonyl) phenoxy] -1,7-dihydropurin-6-one trifluoroacetate

6.86 mg of the title compound was prepared according to the method of Example 210, using pyrrolidone instead of dimethylamine.

MS m / e (ESI) 476 (MH ⁺ -CF ₃ COOH).

Example 213

7- (2-Butynyl) -1-methyl-2- [2- (morpholin-4-carbonyl) phenoxy] -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

3.63 mg of the title compound was prepared according to the method of Example 210, using morpholine instead of dimethylamine.

MS m / e (ESI) 492 (MH ⁺ -CF ₃ COOH).

Example 214

[7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] acetonitrile trifluoroacetate

Example 215

Trifluoroacetate [7- (2-butynyl) -2-cyanomethyl-1-methyl-6-oxo-8- (piperazin-1-yl) -2,3,6,7-tetrahydro-1H-purin-2-yl] acetonitrile

8 mg of 4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylic acid tert-butyl ester was dissolved in 0.8 ml of acetonitrile and then 8 mg of sodium hydride is added to the resulting solution. The mixture is stirred at 60 ° C for three hours. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.85 mg and 2.20 mg of the title compounds (Examples 214) and 215), respectively.

(Example 214) MS m / e (ESI) 326 (MH ⁺ —CF ₃ COOH).

(Example 215) MS m / e (ESI) 367 (MH ⁺ —CF ₃ COOH).

Example 216

7- (2-Butynyl) -1-methyl-2- (2-oxopropyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.8 ml of acetone and 8 mg of sodium hydride is added to the resulting solution. The resulting mixture was stirred at 60 ° C for three hours. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The resulting solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.17 mg of the title compound.

MS m / e (ESI) 343 (MH ⁺ -CF ₃ COOH).

Example 217

7- (2-Butynyl) -2-ethynyl-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

50 μl of trimethylsilylacetylene are dissolved in 1.0 ml of tetrahydrofuran, then 0.27 ml of n-butyllithium (1.56 M solution in hexane) is added at -78 ° C. The mixture was stirred at 0 ° C for 15 minutes and 1.0 ml of a tetrahydrofuran solution containing 10 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo was added to the resulting reaction solution. -6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate. After the resulting mixture was stirred at room temperature for 30 minutes, a saturated solution of ammonium chloride was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 1.0 ml of methanol. 10 mg of potassium carbonate was added to the solution. After the resulting mixture was stirred at room temperature for 1 hour, a saturated solution of ammonium chloride was added. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The resulting solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.06 mg of the title compound.

MS m / e (ESI) 311 (MH ⁺ -CF ₃ COOH).

Example 218

7- (2-Butynyl) -1-methyl-8- (piperazin-1-yl) -2- (propan-2-sulfinyl) -1,7-dihydropurin-6-one trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone and 20 μl of 2-propanethiol and 6 mg of potassium carbonate are added to the solution. The mixture was stirred at room temperature for five hours. A saturated solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 0.30 ml of dichloromethane. The mixture is cooled to -78 ° C. 5 ml of m-chloroperbenzoic acid was added to the mixture, and the resulting mixture was stirred at -78 ° C for 15 minutes. A saturated sodium sulfite solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated and the residue was dissolved in 0.40 ml of trifluoroacetic acid. The solution was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 0.89 mg of the title compound.

MS m / e (ESI) 377 (MH ⁺ -CF ₃ COOH).

Example 219

N-Acetyl-N- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] acetamide trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of 20% aqueous ammonia and the mixture is stirred at 80ºC for 5 hours. The reaction solution was concentrated and the residue was dissolved in 0.4 ml of pyridine. To the mixture was added 0.05 ml of acetic anhydride. The resulting mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 1.49 mg of the title compound.

MS m / e (ESI) 386 (MH ⁺ -CF ₃ COOH).

Example 220

N- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] acetamide trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.2 ml of a 20% aqueous ammonia solution and the mixture is stirred at 80 ° C for 5 hours. The reaction solution was concentrated and the residue was dissolved in 0.4 ml of pyridine. 0.05 ml of acetic anhydride was added to the solution. The resulting mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated and the residue was dissolved in methanol. 10 mg of potassium carbonate was added to the solution. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the resulting residue was purified by reverse phase high performance liquid chromatography (using acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 1.36 mg of the title compound.

MS m / e (ESI) 344 (MH ⁺ -CF ₃ COOH).

Example 221

[7- (2-Butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] acetonitrile trifluoroacetate

8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, and 50 μl of hydroxyacetonitrile and 5 mg of sodium hydride are added to the resulting solution. The mixture was stirred at room temperature for one hour. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The resulting solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using a mixture of acetonitrile-water as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.12 mg of the title compound.

MS m / e (ESI) 342 (MH ⁺ -CF ₃ COOH).

Example 222

N- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yl] guanidine trifluoroacetate

7 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, then 10 mg of guanidine is added. The mixture is stirred at 90 ° C for 12 hours. The reaction solution was concentrated and the residue was dissolved in 1.0 ml of trifluoroacetic acid. The resulting solution was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 3.20 mg of the title compound.

MS m / e (ESI) 344 (MH ⁺ -CF ₃ COOH).

Example 223

7- (2-Butynyl) -2-methylsulfanyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

(a) tert-Butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-1- (2-trimethylsilanylethoxymethyl) -6,7-dihydro-1H-purin-8-yl] piperazine- 1-carboxylate

50 mg of tert-butyl 4- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 1.2 ml N, N-dimethylformamide and 44 μl of (2-chloromethoxyethyl) trimethylsilane and 34 mg of potassium carbonate were added to the resulting solution. The resulting mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography to give 55 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 0.07 (s, 9H), 0.97 (t, J = 8.4 Hz, 2H), 1.49 (s, 9H), 1.82 (t, J = 2.4 Hz, 3H) 3.40-3.44 (m, 4H), 3.58-3.62 (m, 4H), 3.71 (t, J = 8.4 Hz, 2H), 4.92 (q, J = 2.4 Hz, 2H); 5.67 (s, 2H).

(b) 7- (2-Butynyl) -2-methylsulfanyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

6 mg tert-butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-1- (2-trimethylsilanylethoxymethyl) -6,7-dihydro-1H-purin-8-yl] piperazin-1 β-carboxylate is dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, and then 50 μl of methyl mercaptan (30%; methanol solution) and 10 mg of potassium carbonate are added to the resulting solution. The resulting mixture was stirred at room temperature for five hours. A saturated solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 0.60 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 5 hours. Then, the solution was concentrated by purging with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mixture as the mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.99 mg of the title compound.

MS m / e (ESI) 319 (MH ⁺ -CF ₃ COOH).

Example 224

7- (2-Butynyl) -2-isopropylsulfanyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

2.97 mg of the title compound was prepared according to the method of Example 223 using the propan-2-thiol sodium salt instead of methyl mercaptan.

MS m / e (ESI) 347 (MH ⁺ -CF ₃ COOH).

Example 225

2-tert-butylsulfanyl-7- (2-butynyl) -8- (piperazin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

2.99 mg of the title compound was prepared according to the method of Example 223 using the 2-methyl-2-propanethiol sodium salt instead of methyl mercaptan.

MS m / e (ESI) 361 (MH ⁺ -CF ₃ COOH).

Example 226

7- (2-Butynyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-1- (2-trimethylsilanylethoxymethyl) -6,7-dihydro-1H-purin-8-yl] piperazine is dissolved 1-carboxylate in 0.15 ml of 1-methyl-2-pyrrolidone and then 8 mg of sodium cyanide and 10 mg of potassium carbonate are added to the solution. The mixture was stirred at 50ºC for five hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 0.60 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 5 hours. Then the solution is concentrated by flushing it with gaseous nitrogen. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 1.46 mg of the title compound.

MS m / e (ESI) 298 (MH ⁺ -CF ₃ COOH).

Example 227

2- [7- (2-Butynyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide trifluoroacetate

6 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-1- (2-trimethylsilanylethoxymethyl) -6,7-dihydro-1H-purin-8-yl] piperazine is dissolved 1-carboxylate in 0.15 ml of 1-methyl-2-pyrrolidone and then 8 mg of salicylamide and 8 mg of potassium carbonate are added to the solution. The mixture was stirred at 100ºC for three hours. Ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in 0.80 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 5 hours. The solution was concentrated by flushing it with nitrogen gas. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 2.45 mg of the title compound.

MS m / e (ESI) 408 (MH ⁺ -CF ₃ COOH).

Example 228

4- [7- (2-Butynyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzoic acid trifluoroacetate

1.55 mg of the title compound is obtained using 4-hydroxybenzoic acid instead of salicylamide according to the method described in Example 227.

MS m / e (ESI) 409 (MH ⁺ -CF ₃ COOH).

Example 229

7- (2-Butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

(a) tert-Butyl-4- [7- (2-butynyl) -2-cyano-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine- 1-carboxylate

Mixture of 8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl ] piperazine-1-carboxylate obtained in Example 96 (a), 10 mg sodium cyanide and 0.3 ml N, N-dimethylformamide were stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and then with brine. The organic layer is concentrated. The residue was purified by thin layer chromatography (50% ethyl acetate in hexane) to give 6.1 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.83 (s, 3H), 3.50 (s, 4H), 3.58-3.64 (m, 4H), 4.99 (s, 2H), 5.74 (s, 2H), 7.02 (d, J = 8 Hz, 1H), 7.44 (t, J = 8 Hz, 1H), 7.55 (t, J = 8 Hz, 1H) 7.74 (d, J = 8 Hz, 1H).

(b) 7- (2-Butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

A mixture consisting of 6.1 mg of tert-butyl-4- [7- (2-butynyl) -2-cyano-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8 -yl] piperazine-1-carboxylate and 0.2 ml of trifluoroacetic acid are stirred at room temperature for 20 minutes. The reaction mixture was concentrated and the residue was purified by chromatography on a reverse phase column using a solvent containing from 20 to 60% methanol in water (0.1% concentrated hydrochloric acid) to obtain 5.0 mg of the title compound.

¹ H-NMR (DMSO-d ₆ )

δ 1.80 (s, 3H), 3.30 (s, 4H), 3.60-3.70 (m, 4H), 5.09 (s, 2H), 5.60 (s, 2H), 7.27 (d, J = 8 Hz, 1H), 7.54 (t, J = 8 Hz, 1H), 7.68 (t, J = 8 Hz, 1H), 7.94 (d, J = 8 Hz, 1H), 9.36 (br s, 2H).

Example 230

Trifluoroacetate 3- [7- (2-butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] pyridin- 2-carboxylamide

7 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine is dissolved 1-carboxylate in 0.2 ml of 1-methyl-2-pyrrolidone and then 8 mg of 3-hydroxypyridin-2-carboxylamide and 8 mg of potassium carbonate are added to the solution. The mixture was stirred at 100ºC for 2 hours. 1N was added to the reaction mixture. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.93 mg of the title compound.

MS m / e (ESI) 524 (MH ⁺ -CF ₃ COOH).

Example 231

4- [7- (2-Butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzenesulfonamide trifluoroacetate

1.90 mg of the title compound is obtained using 4-hydroxybenzenesulfonamide instead of 3-hydroxypyridine-2-carboxylamide, according to the method described in Example 230.

MS m / e (ESI) 559 (MH ⁺ -CF ₃ COOH).

Example 232

2- [7- (2-Butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzonitrile trifluoroacetate

2.15 mg of the title compound is obtained using 2-cyanophenol instead of 3-hydroxypyridin-2-carboxylamide according to the method described in Example 230.

MS m / e (ESI) 505 (MH ⁺ -CF ₃ COOH).

Example 233

4- [7- (2-Butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzoic acid trifluoroacetate

3.74 mg of the title compound is obtained using 4-hydroxybenzoic acid instead of 3-hydroxypyridin-2-carboxylamide according to the method described in Example 230.

MS m / e (ESI) 524 (MH ⁺ -CF ₃ COOH).

Example 234

2- [7- (2-Butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide trifluoroacetate

3.74 mg of the title compound is obtained using salicylamide instead of 3-hydroxypyridin-2-carboxylamide according to the method described in Example 230.

MS m / e (ESI) 523 (MH ⁺ -CF ₃ COOH).

Example 235

2- [7- (2-Butynyl) -1- (4-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide trifluoroacetate

(a) tert-Butyl-4- [7- (2-butynyl) -2-chloro-1- (4-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine- 1-carboxylate

100 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 1.2 ml N, N-dimethylformamide and then 97 mg of 4-cyanobenzyl bromide and 68 mg of potassium carbonate are added to the solution. The mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain 71 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.84 (t, J = 2.5 Hz, 3H), 3.43-3.47 (m, 4H), 3.59-3.63 (m, 4H ), 4.94 (q, 2.5 Hz, 2H), 5.53 (s, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8 , 0 Hz, 2H).

(b) 2- [7- (2-Butynyl) -1- (4-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy trifluoroacetate ] benzamide

12 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1- (4-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine is dissolved 1-carboxylate in 0.3 ml of 1-methyl-2-pyrrolidone and then 10 mg of salicylamide and 10 mg of potassium carbonate are added to the solution. The mixture was stirred at 100ºC for 12 hours. 1N was added to the reaction mixture. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 6.69 mg of the title compound.

MS m / e (ESI) 523 (MH ⁺ -CF ₃ COOH).

Example 236

7- (2-Butynyl) -1- (4-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile trifluoroacetate

12 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1- (4-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine is dissolved 1-carboxylate in 0.3 ml of 1-methyl-2-pyrrolidone and then 10 mg of sodium cyanide are added to the solution. The mixture was stirred at 50 ° C for 2 hours. Add to the reaction solution 1 N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 3.87 mg of the title compound.

MS m / e (ESI) 413 (MH ⁺ -CF ₃ COOH).

Example 237

4- [7- (2-Butynyl) -2-methylsulfanyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydropurin-1-ylmethyl] benzonitrile trifluoroacetate

12 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1- (4-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine is dissolved 1-carboxylate in 0.3 ml of 1-methyl-2-pyrrolidone and then 20 μl of methyl mercaptan (30%; methanol solution) and 10 mg of potassium carbonate are added to the solution. The mixture was stirred at 50 ° C for 2 hours. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 6.69 mg of the title compound.

MS m / e (ESI) 434 (MH ⁺ -CF ₃ COOH).

Example 238

2- [7- (2-Butynyl) -1- (3-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide trifluoroacetate

(a) tert-Butyl-4- [7- (2-butynyl) -2-chloro-1- (3-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine- 1-carboxylate

100 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate is dissolved in 1.2 ml N, N-dimethylformamide and then 97 mg of 3-cyanobenzyl bromide and 68 mg of potassium carbonate are added to the solution. The mixture was stirred at room temperature for 12 hours. Then, a saturated solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by silica gel column chromatography to obtain 71 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.84 (t, J = 2.5 Hz, 3H), 3.43-3.47 (m, 4H), 3.59-3.63 (m, 4H ), 4.94 (q, 2.5 Hz, 2H), 5.53 (s, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8 , 0 Hz, 2H).

(b) 2- [7- (2-Butynyl) -1- (3-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy trifluoroacetate ] benzamide

12 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1- (3-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine is dissolved 1-carboxylate in 0.3 ml of 1-methyl-2-pyrrolidone and then 10 mg of salicylamide and 10 mg of potassium carbonate are added to the solution. The mixture is stirred at 100ºC for five hours. Add to the reaction solution 1 N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 8.76 mg of the title compound.

Mass spectrum m / e (ESI) 523 (MH ⁺ —CF ₃ COOH).

Example 239

Trifluoroacetate 7- (2-butynyl) -1- (3-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile

12 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-1- (3-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine is dissolved 1-carboxylate in 0.3 ml of 1-methyl-2-pyrrolidone and then 10 mg of sodium cyanide are added to the solution. The mixture was stirred at 50 ° C for 1 hour. Add to the reaction solution 1 N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.96 mg of the title compound.

MS m / e (ESI) 413 (MH ⁺ -CF ₃ COOH).

Example 240

1- (2-Butynyl) -2- (piperazin-1-yl) -7,8-dihydro-1H hydrochloride, 6H-5-oxa-1,3,4,8a-tetraazacyclopenta [b] naphthalen-9-one

(a) tert-Butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-1- [3- (tetrahydropyran-2-yloxy) propyl] -6,7-dihydro-1H-purine -8-yl] piperazine-1-carboxylate

A mixture consisting of 20 mg of tert-butyl 4- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate obtained in Example 95 (a), 20 μl of 2- (3-bromopropoxy) tetrahydropyran, 20 mg of anhydrous potassium carbonate and 0.2 ml of N, N-dimethylformamide were stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate-water, and the organic layer was washed with water and then with brine. The organic layer was then concentrated and the residue was purified by thin layer chromatography (70% ethyl acetate in hexane) to give 8 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.50-1.81 (m, 6H), 1.83 (t, J = 2 Hz, 3H), 2.06 (q, J = 7 Hz, 2H) , 3.38-3.62 (m, 10H), 3.80-3.90 (m, 2H), 4.34-4.47 (m, 2H), 4.59 (t, J = 3 Hz , 1H); 4.92 (q, J = 2 Hz, 2H).

(b) tert-Butyl-4- [1- (2-butynyl) -9-oxo-1,7,8,9-tetraazacyclopenta [b] naphthalene-2-yl] piperazine-1-carboxylate

A mixture of 8 mg of tert-butyl-4- [7- (2-butynyl) -2-chloro-6-oxo-1- [3- (tetrahydropyran-2-yloxy) propyl] -6,7-dihydro 1H-purin-8-yl] piperazine-1-carboxylate, 0.2 ml of ethanol and a catalytic amount of p-toluenesulfonic acid monohydrate were stirred at room temperature for 4 hours and then 40 mg of anhydrous potassium carbonate was added to the solution. The mixture was further stirred overnight. The reaction solution was extracted with ethyl acetate-water, and the organic layer was washed with water and then with brine. The organic layer was then concentrated and the residue was purified by thin layer chromatography (20% methanol in ethyl acetate) to obtain 3 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.82 (t, J = 2 Hz 3H), 2.18-2.26 (m, 2H), 3.37-3.43 (m, 4H), 3 , 56-3.62 (m, 4H), 4.07 (t, J = 6 Hz, 2H), 4.43 (t, J = 5 Hz, 2H), 4.88 (q, J = 2 Hz , 2H).

(c) 1- (2-Butynyl) -2- (piperazin-1-yl) -7,8-dihydro-1H, 6H-5-oxa-1,3,4,8a-tetraazacyclopenta [b] naphthalene hydrochloride 9th

A mixture consisting of 3 mg of tert-butyl 4- [1- (2-butynyl) -9-oxo-1,7,8,9-tetraazacyclopenta [b] naphthalen-2-yl] piperazine-1-carboxylate and 0 5 ml of trifluoroacetic acid, stirred at room temperature for 20 minutes. The solution was then concentrated and the residue was purified on a reverse phase chromatography column using a solvent of 20 to 50% methanol in water (0.1% concentrated hydrochloric acid) to obtain 2.1 mg of the title compound.

¹ H-NMR (DMSO-d ₆ )

δ 1.79 (s, 3H), 2.08-2.16 (m, 2H), 3.27 (br s, 4H), 3.44-3.54 (m, 4H), 3.90 (t, J = 6 Hz, 2H), 4.38 (t, J = 5 Hz, 2H), 4.94 (s, 2H), 9.02 (br s, 2H).

Example 241

1- (2-Butynyl) -2- (piperazin-1-yl) -6,7-dihydro-1H-5-oxa-1,3,4,7a-tetraaza-sim-indacen-8-one hydrochloride

In Example 240, the title compound was prepared using 2- (2-bromoethoxy) tetrahydropyran instead of 2- (3-bromopropoxy) tetrahydropyran, according to the method described in Example 240.

¹ H-NMR (DMSO-d ₆ )

δ 1.80 (s, 3H), 3.27 (br.s, 4H), 4.19 (t, J = 8 Hz, 2H), 4.70 (t, J = 8 Hz, 2H), 4 94 (s, 2H); 9.06 (br s, 2H).

Example 242

8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

(a) Benzyl 3-tert-butoxycarbonylaminopiperidine-1-carboxylate

88 g of benzyl chloroformate (30% solution in toluene) are added dropwise to a mixture of 24.3 g of ethyl piperidine-3-carboxylate, 26 ml of triethylamine and 300 ml of ethyl acetate, over 30 minutes while cooling the mixture with ice. The reaction mixture is filtered in order to remove insoluble matter. The filtrate is again filtered through a small layer of silica gel. The filtrate was concentrated.

200 ml of ethanol and 40 ml of an aqueous solution of (5 M) sodium hydroxide are added to the residue. The mixture was stirred at room temperature overnight. The reaction solution was concentrated and 200 ml of water was added to the residue. The mixture was extracted with methyl tert-butyl ether. A 5 M aqueous hydrochloric acid solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to give an oily residue (30.9 g).

A mixture consisting of 30 g of this residue, 24.5 ml of diphenylphosphoryl azide, 15.9 ml of triethylamine and 250 ml of tert-butanol was stirred at room temperature for 1.5 hours. The mixture is further stirred in an oil bath at 100ºC for 20 hours. The reaction solution was concentrated and the residue was extracted with ethyl acetate-water. The organic layer was washed with dilute aqueous sodium bicarbonate and then with brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography using a solvent of 10 to 20% ethyl acetate in hexane, and subsequent recrystallization from ethyl acetate-hexane gave 21.4 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.43 (s, 9H), 1.48-1.92 (m, 4H), 3.20-3.80 (m, 5H), 4.58 (br s, 1H), 5.13 (s, 2H); 7.26-7.40 (m, 5H).

(b) tert-butyl-piperidin-3-ylcarbamate

A mixture consisting of 10 g of benzyl-3-tert-butoxycarbonylaminopiperidine-1-carboxylate, 500 mg of catalyst — 10% palladium-carbon — and 100 ml of ethanol was stirred at room temperature in a hydrogen atmosphere overnight. The catalyst is removed by filtration. The filtrate was concentrated and dried, yielding 6.0 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.44 (s, 9H), 1.47-1.80 (m, 4H), 2.45-2.60 (m, 1H), 2.60-2.75 (m, 1H), 2 , 75-2.90 (m, 1H), 3.05 (dd, J = 3 Hz, 12 Hz, 1H), 3.57 (br.s, 1H), 4.83 (br.s, 1H) .

(c) tert-Butyl- [1- [7- (2-butynyl) -2,6-dichloro-7H-purin-8-yl] piperidin-3-yl] carbamate

A mixture of 1.25 g of 7- (2-butynyl) -2,6,8-trichloro-7H-purine, 1.0 g of tert-butylpiperidin-3-ylcarbamate and 10 ml of acetonitrile was stirred at room temperature for 10 minutes. 0.63 ml of triethylamine are added dropwise over 10 minutes and then the mixture is continuously stirred at room temperature for 30 minutes. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue crystallizes from methyl tert-butyl ether-hexane to give 1.79 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.43 (s, 9H), 1.60-2.02 (m, 4H), 1.83 (t, J = 2 Hz, 3H), 3.32-3.41 (m, 1H), 3.42-3.52 (m, 1H), 3.67-3.76 (m, 1H), 3.80-3.91 (m, 1H), 4.76-4.90 (m, 3H) )

(d) tert-Butyl- [1- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] carbamate

A mixture consisting of 1.79 g of tert-butyl- [1- [7- (2-butynyl) -2,6-dichloro-7H-purin-8-yl] piperidin-3-yl] carbamate, 1.0 g sodium acetate and 18 ml of dimethyl sulfoxide, stirred in an oil bath at 120ºC for three hours. This mixture was removed from the oil bath and 18 ml of water was added to the reaction solution. The mixture was cooled to room temperature. The crystals were collected by filtration and washed with water and then with methyl tert-butyl ether. Then, the crystals were dried, yielding 1.59 g of the title compound.

¹ H-NMR (DMSO-d ₆ )

δ 1.39 (s, 9H), 1.34-1.88 (m, 4H), 1.78 (s, 3H), 2.81 (t, J = 11 Hz, 1H), 2.95 ( t, J = 11 Hz, 1H), 3.48-3.60 (m, 2H), 3.64 (d, J = 6 Hz, 1H), 4.90 (s, 2H), 6.94 ( d, J = 8 Hz, 1H).

(e) tert-Butyl- [1- [7- (2-butynyl) -2-chloro-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperidine -3-yl] carbamate

Mixture consisting of 100 mg of tert-butyl- [1- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] carbamate, 66 mg of anhydrous potassium carbonate, 70 mg of 2-cyanobenzyl bromide and 1 ml of N, N-dimethylformamide are stirred at room temperature for five hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography using a solvent of 50% ethyl acetate in hexane; 44.7 mg of the title compound are obtained.

¹ H-NMR (CDCl ₃ )

δ 1.44 (s, 9H), 1.59-1.81 (m, 2H), 1.83 (t, J = 2 Hz, 3H), 1.86-1.94 (m, 2H), 3.20-3.50 (m, 3H), 3.66 (d, J = 7 Hz, 1H), 3.86 (br s, 1H), 4.88-5.06 (m, 3H) 5.72 (s, 2H), 7.06 (d, J = 8 Hz, 1H), 7.38 (t, J = 8 Hz, 1H), 7.51 (t, J = 8 Hz, 1H ), 7.70 (d, J = 8 Hz, 1H).

(f) tert-Butyl- [1- [7- (2-butynyl) -2-cyano-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1-purin-8-yl] piperidine -3-yl] carbamate

Mixture of 15 mg of tert-butyl- [1- [7- (2-butynyl) -2-chloro-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8- il] piperidin-3-yl] carbamate, 20 mg of sodium cyanide and 0.2 ml of N, N-dimethylformamide, stirred at room temperature for three hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with brine. Then the organic layer was concentrated and the residue was purified by thin-layer chromatography using a solvent of 50% ethyl acetate in hexane (three times), and 10.3 mg of the title compound was obtained.

¹ H-NMR (CDCl ₃ )

δ 1.44 (s, 9H), 1.52-1.98 (m, 4H), 1.81 (t, J = 2 Hz 3H), 3.24 (dd, J = 7 Hz, 12 Hz, 1H), 3.30-3.40 (m, 1H), 3.46-3.56 (m, 1H), 3.72 (d, J = 12 Hz, 1H), 3.86 (br.s , 1H), 4.86-5.10 (m, 3H), 5.73 (s, 2H), 7.00 (d, J = 8 Hz, 1H), 7.42 (t, J = 8 Hz , 1H), 7.54 (dt, J = 2 Hz, 8 Hz, 1H), 7.73 (dd, J = 2 Hz, 8 Hz, 1H).

(g) 8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

A mixture consisting of 10.3 mg of tert-butyl- [1- [7- (2-butynyl) -2-cyano-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purine- 8-yl] piperidin-3-yl] carbamate and 0.2 ml of trifluoroacetic acid are stirred for 20 minutes. The reaction solution was concentrated and the residue was purified by chromatography on a reverse phase column using a solvent of 20 to 80% methanol in water (0.1% concentrated hydrochloric acid), and 8.0 mg of the title compound was obtained.

¹ H-NMR (DMSO-d ₆ )

δ 1.60-1.74 (m, 2H), 1.79 (t, J = 2 Hz, 3H), 1.88-2.03 (m, 2H), 3.14-3.28 (m , 2H), 3.42 (br s, 1H), 3.52-3.82 (m, 2H), 4.98-5.12 (m, 2H), 5.58 (s, 2H), 7.26 (d, J = 8 Hz, 1H), 7.53 (t, J = 8 Hz, 1H), 7.66 (t, J = 8 Hz, 1H), 7.93 (d, J = 8 Hz, 1H), 8.16 (br s, 3H).

Example 243

2- [8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -2-methoxy-6-oxo-6,7-dihydropurin-1-ylmethyl] benzonitrile hydrochloride

Mixture of 15 mg of tert-butyl- [1- [7- (2-butynyl) -2-chloro-1- (2-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8- il] piperidin-3-yl] carbamate, 20 mg of anhydrous potassium carbonate and 0.2 ml of methanol, is stirred for three hours. Subsequent steps are carried out according to the same method as used in Example 242, steps (f) and (g). In this way, the title compound is synthesized.

¹ H-NMR (DMSO-d ₆ )

δ 1.58-1.72 (m, 2H), 1.84-1.94 (m, 1H), 1.96-2.04 (m, 1H), 3.08-3.20 (m, 2H), 3.36-3.70 (m, 3H), 3.90 (s, 3H), 4.90-5.02 (m, 2H), 5.32 (s, 2H), 7.20 (d, J = 8 Hz, 1H), 7.47 (t, J = 8 Hz, 1H), 7.63 (t, J = 8 Hz, 1H), 7.87 (d, J = 8 Hz, 1H), 8.12 (br s, 3H).

Example 244

8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -6-oxo-1- (2-phenylethyl) -6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

(a) tert-Butyl- [1- [7- (2-butynyl) -2-chloro-6-oxo-1- (2-phenylethyl) -6,7-dihydro-1H-purin-8-yl] piperidine -3-yl] carbamate

The title compound was prepared using 2-bromoethylbenzene instead of 2-cyanobenzyl bromide according to the method described in Example 242 (e).

¹ H-NMR (CDCl ₃ )

δ 1.44 (s, 9H), 1.58-1.80 (m, 2H), 1.83 (t, J = 2 Hz, 3H), 1.86-1.94 (m, 2H), 3.00-3.06 (m, 2H), 3.20-3.50 (m, 3H), 3.60 (d, J = 12 Hz, 1H), 3.85 (br s, 1H) 4.42-4.48 (m, 2H); 4.88-5.04 (m, 3H); 7.02-7.34 (m, 5H).

(b) 8- (3-Aminopiperidin-1-yl) -7- (2-butynyl) -6-oxo-1- (2-phenylethyl) -6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

The title compound was synthesized using tert-butyl- [1- [7- (2-butynyl) -2-chloro-6-oxo-1- (2-phenylethyl) -6,7-dihydro-1H-purine -8-yl] piperidin-3-yl] carbamate according to the method described in example 242 (f) and (g).

¹ H-NMR (DMSO-d ₆ )

δ 1.60-1.72 (m, 2H), 1.83 (s, 3H), 1.88-2.06 (m, 3H), 3.04 (t, J = 7 Hz, 2H), 3.35-3.60 (m, 2H), 3.75 (d, J = 12 Hz, 1H), 4.35 (t, J = 7 Hz, 2H), 5.09 (s, 2H), 7.18 (d, J = 7 Hz, 2H), 7.22-7.34 (m, 3H), 8.16 (br s, 3H).

Example 245

8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -2-methoxy-1- (2-phenylethyl) -1,7-dihydropurin-6-one hydrochloride

The title compound was synthesized using tert-butyl- [1- [7- (2-butynyl) -2-chloro-6-oxo-1- (2-phenylethyl) -6,7-dihydro-1H-purine -8-yl] piperidin-3-yl] carbamate according to the method described in example 243.

¹ H-NMR (DMSO-d ₆ )

δ 1.56-1.72 (m, 2H), 1.80 (t, J = 2 Hz, 3H), 1.84-2.04 (m, 2H), 2.85 (t, J = 7 Hz, 2H), 3.08-3.18 (m, 2H), 3.34-3.54 (m, 2H), 3.64 (d, J = 12 Hz, 1H), 3.83 (s , 3H), 4.15 (t, J = 7 Hz, 2H), 4.88-5.02 (m, 2H), 7.16-7.24 (m, 3H), 7.29 (t, J = 7 Hz, 2H), 8.09 (br s, 3H).

Example 246

8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -1- (4-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

(a) tert-Butyl- [1- [7- (2-butynyl) -2-chloro-1- (4-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purin-8-yl] piperidine -3-yl] carbamate

The title compound was prepared using 4-cyanobenzyl bromide instead of 2-cyanobenzyl bromide according to the method described in Example 242 (e).

¹ H-NMR (CDCl ₃ )

δ 1.44 (s, 9H), 1.58-1.80 (m, 2H), 1.82 (t, J = 2 Hz, 3H), 1.85-1.95 (m, 2H), 3.18-3.26 (m, 1H), 3.29-3.37 (m, 1H), 3.40-3.48 (m, 1H), 3.65 (d, J = 12 Hz, 1H), 3.86 (br.s, 1H), 4.86-5.04 (m, 3H), 5.22 (s, 2H), 7.41 (d, J = 8 Hz, 2H), 7.62 (d, J = 8 Hz, 2H).

(b) 8- (3-Aminopiperidin-1-yl) -7- (2-butynyl) -1- (4-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

The title compound was synthesized using tert-butyl- [1- [7- (2-butynyl) -2-chloro-1- (4-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purine -8-yl] piperidin-3-yl] carbamate, according to the method described in example 242 (f) and (g).

¹ H-NMR (DMSO-d ₆ )

δ 1.62-1.72 (m, 2H), 1.80 (s, 3H), 1.88-1.96 (m, 1H), 1.98-2.06 (m, 1H), 3 , 16-3.26 (m, 2H), 3.41 (br s, 1H), 3.50-3.80 (m, 2H), 5.07 (s, 2H), 5.49 (s , 2H), 7.49 (d, J = 8 Hz, 2H), 7.85 (d, J = 8 Hz, 2H), 8.16 (br s, 3H).

Example 247

4- [8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -2-methoxy-6-oxo-6,7-dihydropurin-1-ylmethyl] benzonitrile hydrochloride

The title compound was synthesized using tert-butyl [1- [7- (2-butynyl) -2-chloro-1- (4-cyanobenzyl) -6-oxo-6,7-dihydro-1H-purine- 8-yl] piperidin-3-yl] carbamate according to the method described in example 243.

¹ H-NMR (DMSO-d ₆ )

δ 1.58-1.70 (m, 2H), 1.79 (s, 3H), 1.84-2.04 (m, 2H), 3.08-3.20 (m, 2H), 3 , 36-3.70 (m, 3H), 3.89 (s, 3H), 4.88-5.02 (m, 2H), 5.22 (s, 2H), 7.39 (d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H), 8.14 (br s, 3H).

Example 248

The salt of 2- [8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -1-methyl-6-oxo-6,7-dihydro-1H-purin-2-yloxy] benzamide trifluoroacetic acid

(a) tert-Butyl [1- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] carbamate

700 mg of tert-butyl [1- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] carbamate is dissolved in 7, 0 ml of dimethyl sulfoxide and then 114 μl of methyl iodide and 299 mg of potassium carbonate are added to the solution. The mixture was stirred at room temperature for 30 minutes and 40 ml of water was added to the reaction solution. The mixture was stirred at room temperature for 30 minutes and the resulting white precipitate was collected by filtration. The resulting white solid was washed with water and then with hexane, to give 540 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.44 (s, 9H), 1.72-1.94 (m, 4H), 1.81 (t, J = 2.4 Hz, 3H), 3.16-3.92 (m, 5H) ), 3.72 (s, 3H), 4.91 (dd, J = 17.6, 2.4 Hz, 1H), 5.01 (d, J = 17.6 Hz, 1H).

(b) 2- [8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -1-methyl-6-oxo-6,7-dihydro-1H-purin-2-yloxy] benzamide trifluoroacetate

10 mg of tert-butyl [1- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] is dissolved carbamate in 0.3 ml of 1-methyl-2-pyrrolidone and then 10 mg of salicylamide and 10 mg of potassium carbonate are added to this solution. The mixture was stirred at 100ºC for 2 hours. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 5.54 mg of the title compound.

MS m / e (ESI) 436 (MH ⁺ -CF ₃ COOH).

Example 249

8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -1-methyl-6-oxo-6,7-dihydro-1H-purine-2-carbonitrile trifluoroacetate

10 mg of tert-butyl [1- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] is dissolved carbamate in 0.3 ml of 1-methyl-2-pyrrolidone and then 10 mg of sodium cyanide are added to the solution. The mixture was stirred at 60 ° C for 2 hours. Add to the reaction solution 1 N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 3.67 mg of the title compound.

MS m / e (ESI) 326 (MH ⁺ -CF ₃ COOH).

Example 250

8- (3-aminopiperidin-1-yl) -2-tert-butylsulfanyl-7- (2-butynyl) -1-methyl-1,7-dihydropurin-6-one trifluoroacetate

10 mg of tert-butyl [1- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] is dissolved carbamate in 0.3 ml of 1-methyl-2-pyrrolidone and then 10 mg of 2-methyl-2-propanethiol sodium salt is added to the solution. The mixture was stirred at room temperature for 2 hours. Add to the reaction solution 1 N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 5.00 mg of the title compound.

MS m / e (ESI) 389 (MH ⁺ -CF ₃ COOH).

Example 251

8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -2-methoxy-1-methyl-1,7-dihydropurin-6-one trifluoroacetate

10 mg of tert-butyl [1- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] is dissolved carbamate in 0.6 ml of methanol and then 8 mg of sodium hydride are added to the solution. The mixture was stirred at room temperature for 1 hour. To the reaction solution was added 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer was concentrated and the residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 2.14 mg of the title compound.

MS m / e (ESI) 331 (MH ⁺ -CF ₃ COOH).

Example 252

8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -2-diethylamino-1-methyl-1,7-dihydropurin-6-one trifluoroacetate

10 mg of tert-butyl [1- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] is dissolved carbamate in 0.3 ml of 1-methyl-2-pyrrolidone and then 50 μl of diethylamine are added to the solution. The mixture was stirred at 60 ° C for 4 hours. Add 1 N. hydrochloric acid to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the resulting residue was dissolved in trifluoroacetic acid. The solution was concentrated and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 2.17 mg of the title compound.

MS m / e (ESI) 372 (MH ⁺ -CF ₃ COOH).

Example 253

8- (3-aminopiperidin-1-yl) -7- (2-butynyl) -1-methyl-2- (pyrrolidin-1-yl) -1,7-dihydropurin-6-one trifluoroacetate

Using pyrrolidine, instead of diethylamine, 1.94 mg of the title compound are obtained according to the method described in Example 252.

MS m / e (ESI) 370 (MH ⁺ -CF ₃ COOH).

Example 254

8- (3-Methylaminopiperidin-1-yl) -7- (2-butynyl) -1-methyl-6-oxo-6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

(a) tert-Butyl-N-methyl-N- (piperidin-3-yl) carbamate

0.4 g of sodium hydride (60%; suspension in oil) is added to a mixture consisting of 3.3 g of 3-tert-butoxycarbonylaminopiperidine-1-carboxylate, 0.75 ml of methyl iodide and 20 ml of N, N-dimethylformamide, in water bath at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography using a solvent of 10 to 20% ethyl acetate in hexane to give an oily material (3.04 g). The entire amount of material is combined with 20 ml of ethanol and a catalyst - 10% palladium on charcoal. This mixture was stirred at room temperature under a hydrogen atmosphere for five hours. After removal of the catalyst by filtration, the filtrate was concentrated to obtain 1.82 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.46 (s, 9H), 1.48-1.64 (m, 2H), 1.72-1.84 (m, 2H), 2.43 (dt, J = 3 Hz, 12 Hz, 1H), 2.60 (t, J = 12 Hz, 1H), 2.75 (s, 3H), 2.74-3.02 (m, 2H), 3.86 (br s, 1H).

(b) tert-Butyl-N- [1- [7- (2-butynyl) -2,6-dichloro-7H-purin-8-yl] piperidin-3-yl] -N-methylcarbamate

The title compound was synthesized using 7- (2-butynyl) -2,6,8-trichloro-7H-purine and tert-butylpiperidin-3-ylcarbamate according to the method described in example 242 (c).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.70-2.02 (m, 7H), 2.83 (s, 3H), 3.00 (t, J = 12 Hz, 1H), 3.14 ( t, J = 12 Hz, 1H), 3.96-4.25 (m, 3H), 4.80 (s, 2H).

(c) tert-Butyl-N- [1- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3 -yl] -N-methylcarbamate

Mixture of 580 mg of tert-butyl-N- [1- [7- (2-butynyl) -2,6-dichloro-7H-purin-8-yl] piperidin-3-yl] -N-methylcarbamate, 315 mg of sodium acetate and 6 ml of dimethyl sulfoxide, stirred in an oil bath at 120ºC for 7 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with brine. The organic layer is dried over anhydrous magnesium sulfate, filtered through a small layer of silica gel. The filtrate was concentrated, the residue was crystallized from ethyl acetate-hexane to give 420 mg of tert-butyl-N- [1- [7- (2-butynyl) -2-chloro-6-oxo-6,7-dihydro-1H-purine- 8-yl] piperidin-3-yl] -N-methylcarbamate. A mixture consisting of an aliquot (100 mg) of the above compound, 0.17 ml of methyl iodide, 48 mg of anhydrous potassium carbonate and 0.5 ml of N, N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with brine. The organic layer was then concentrated and the residue was purified by silica gel column chromatography using a solvent of 50% ethyl acetate in hexane to obtain 104 mg of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.47 (s, 9H), 1.62-1.74 (m, 1H), 1.81 (t, J = 2 Hz, 3H), 1.82-1.96 (m, 3H), 2.82 (s, 3H), 2.86 (t, J = 12 Hz, 1H), 3.02 (t, J = 12 Hz, 1H), 3.68-3.82 (m, 2H), 3.72 (s, 3H); 4.20 (br s, 1H); 4.90 (s, 2H).

(d) 7- (2-Butynyl) -1-methyl-8- (3-methylaminopiperidin-1-yl) -6-oxo-6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

Using tert-butyl-N- [1- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl ] -N-methylcarbamate, the title compound is synthesized according to the method described in example 242 (f) and (g).

¹ H-NMR (DMSO-d ₆ )

δ 1.60-1.77 (m, 2H), 1.81 (s, 3H), 1.84-2.00 (m, 1H), 2.02-2.12 (m, 1H), 2 60 (t, J = 5 Hz, 3H), 3.17-3.40 (m, 3H), 3.46-3.56 (m, 1H), 3.79 (d, J = 12 Hz, 1H), 5.00-5.15 (m, 2H), 9.01 (br s, 2H).

Example 255

2- [7- (2-Butynyl) -1-methyl-8- (3-methylaminopiperidin-1-yl) -6-oxo-6,7-dihydro-1H-purin-2-yloxy] benzamide hydrochloride

A mixture consisting of 20 mg of tert-butyl-N- [1- [7- (2-butynyl) -2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl] piperidin-3-yl] -N-methylcarbamate, 20 mg of 2-hydroxybenzamide, 20 mg of anhydrous potassium carbonate and 0.3 ml of N-methyl-2-pyrrolidone, stirred in an oil bath at 80 ° C for 4 hours. The subsequent synthesis steps were carried out in accordance with the same method as that used in Example 242 (f) and (g) in order to obtain the title compound.

¹ H-NMR (DMSO-d ₆ )

δ 1.69 (br s, 2H), 1.82 (s, 3H), 1.92 (br, 1H), 2.07 (br, 1H), 2.62 (s, 3H) ), 3.10-3.40 (m, 4H), 3.48 (s, 3H), 3.76 (br s, 1H), 5.02 (br s, 2H), 6.96 ( broad s, 2H), 7.44 (broad s, 1H), 7.91 (broad s, 1H), 8.81 (broad s, 2H).

Example 256

8- (3-aminopyrrolidin-1-yl) -7- (2-butynyl) -1-methyl-6-oxo-6,7-dihydro-1H-purine-2-carbonitrile hydrochloride

The title compound was synthesized using tert-butylpyrrolidin-3-ylcarbamate instead of tert-butyl-N-methyl-N- (piperidin-3-yl) carbamate in Example 254, according to the method described in Example 254 of Step (b) ), (c) and (d).

¹ H-NMR (DMSO-d ₆ )

δ 1.81 (s, 3H), 2.13 (br s, 1H), 2.32 (br s, 1H), 3.64 (s, 3H), 3.74-3.86 (m , 2H), 3.93 (br s, 3H), 5.19 (d, J = 18 Hz, 1H), 5.28 (d, J = 18 Hz, 1H), 8.32 (br s , 3H).

Example 257

2- [8- (3-aminopyrrolidin-1-yl) -7- (2-butynyl) -1-methyl-6-oxo-6,7-dihydro-1H-purin-2-yloxy] benzamide hydrochloride

The title compound was synthesized using 2-hydroxybenzamide according to the method described in examples 255 and 256.

¹ H-NMR (DMSO-d ₆ )

δ 1.82 (s, 3H), 2.11 (br s, 1H), 2.32 (br s, 1H), 3.46 (s, 3H), 3.72-4.00 (m , 5H), 5.15 (d, J = 19 Hz, 1H), 5.23 (d, J = 19 Hz, 1H), 6.90-7.02 (m, 2H), 7.42-7 50 (m, 1H); 7.90-7.99 (m, 1H); 8.22 (br s, 3H).

Example 258

3- (2-Butynyl) -2- (piperazin-1-yl) -5- (2-propynyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) tert-Butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate

0.299 g of triethylamine, 0.023 g of 4-dimethylaminopyridine and 0.645 g of di-tert-butyl dicarbonate are added to a solution of 0.448 g of 3- (2-butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo trifluoroacetate [4,5 -d] pyridazin-4-one in 20 ml of N, N-dimethylformamide at room temperature and the mixture was stirred for five hours. Then add to this solution 2 ml of 5 N. aqueous sodium hydroxide solution and the mixture is stirred for 1 hour. The reaction solution was poured into a mixture of 200 ml of ethyl acetate and 100 ml of a saturated aqueous solution of ammonium chloride. The organic layer was washed twice with water (100 ml) and then with a saturated solution of sodium chloride (100 ml). The organic liquid was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.298 g of the title compound was obtained from the fraction eluted with ethyl acetate.

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.84 (t, J = 2.3 Hz, 3H), 3.41 (m, 4H), 3.63 (m, 4H), 5.06 (q, J = 2.3 Hz, 2H), 8.17 (s, 1H), 9.92 (br s, 1H).

( b) 3- (2-Butynyl) -2- (piperazin-1-yl) -5- (2-propynyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

0.005 g of potassium carbonate and 0.003 ml of 3-bromo-1-propine are added to a solution of 0.010 g of tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4, 5-d] pyridazin-2-yl] piperazin-1-carboxylate in 0.5 ml of N, N-dimethylformamide and the mixture was stirred at room temperature for 10 hours. 1 ml of ethyl acetate and 1 ml of water are added to the reaction solution, and the layers are separated. The organic layer was concentrated and the resulting residue was dissolved in a mixture of 0.5 ml of dichloromethane and 0.5 ml of trifluoroacetic acid. The mixture was stirred for 1 hour and then concentrated. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.011 g of the title compound.

MS m / e (ESI) 311.29 (MH ⁺ -CF ₃ COOH).

Example 259

[3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-yl] acetonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and bromoacetonitrile according to the method described in example 258 (b).

MS m / e (ESI) 312.28 (MH ⁺ -CF ₃ COOH).

Example 260

3- (2-Butynyl) -5- (2-hydroxyethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromoethanol according to the method described in example 258 (b).

MS m / e (ESI) 317.30 (MH ⁺ -CF ₃ COOH).

Example 261

3- (2-Butynyl) -5- (2-methoxyethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and bromoethyl methyl ether according to the method described in example 258 (b).

MS m / e (ESI) 331.32 (MH ⁺ -CF ₃ COOH).

Example 262

Ethyl [3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-yl] acetate trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and ethyl bromoacetate according to the method described in example 258 (b).

MS m / e (ESI) 359.13 (MH ⁺ -CF ₃ COOH).

Example 263

3- (2-Butynyl) -5- (2-phenylethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and (2-bromoethyl) benzene according to the method described in example 258 (b).

MS m / e (ESI) 377.34 (MH ⁺ -CF ₃ COOH).

Example 264

3- (2-Butynyl) -5- (2-phenoxyethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromoethylphenyl ether according to the method described in example 258 (b).

MS m / e (ESI) 393.32 (MH ⁺ -CF ₃ COOH).

Example 265

3- (2-Butynyl) -5- (2-oxo-2-phenylethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromoacetophenone according to the method described in example 258 (b).

MS m / e (ESI) 391.32 (MH ⁺ -CF ₃ COOH).

Example 266

3- (2-Butynyl) -5- [2- (3-methoxyphenyl) -2-oxoethyl] -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4 trifluoroacetate -she

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromo-3'-methoxyacetophenone according to the method described in example 258 (b).

MS m / e (ESI) 421.33 (MH ⁺ -CF ₃ COOH).

Example 267

2- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromomethylbenzonitrile according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 1.81 (t, J = 2.5 Hz, 3H), 3.45-3.49 (m, 4H), 3.66-3.70 (m, 4H), 5.15 (q, J = 2.5 Hz, 2H), 5.62 (s, 2H), 7.34 (dd, J = 7.6, 1.5 Hz, 1H), 7.45 (td, J = 7.6, 1.5 Hz, 1H), 7.59 (td, J = 7.6, 1.7 Hz, 1H), 7.75 (dd, J = 7.6, 1.7 Hz, 1H), 8, 25 (s, 1H).

Mass spectrum m / e (ESI) 388.32 (MH ⁺ —CF ₃ COOH).

Example 268

3- (2-Butynyl) -2- (piperazin-1-yl) -5- (2-trifluoromethylbenzyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2- (trifluoromethyl) benzyl bromide according to the method described in example 258 (b).

MS m / e (ESI) 431.21 (MH ⁺ -CF ₃ COOH).

Example 269

3- (2-Butynyl) -2- (piperazin-1-yl) -5- (3-trifluoromethylbenzyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 3- (trifluoromethyl) benzyl bromide according to the method described in example 258 (b).

MS m / e (ESI) 431.23 (MH ⁺ -CF ₃ COOH).

Example 270

3- (2-Butynyl) -5- (2-nitrobenzyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-nitrobenzyl bromide according to the method described in example 258 (b).

MS m / e (ESI) 408.25 (MH ⁺ -CF ₃ COOH).

Example 271

3- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 3-bromomethylbenzonitrile according to the method described in example 258 (b).

MS m / e (ESI) 388.27 (MH ⁺ -CF ₃ COOH).

Example 272

4- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4-bromomethylbenzonitrile according to the method described in example 258 (b).

MS m / e (ESI) 388.29 (MH ⁺ -CF ₃ COOH).

Example 273

Methyl 3- [3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzoate trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and methyl 3- (bromomethyl) benzoate according to the method described in example 258 (b).

MS m / e (ESI) 421.29 (MH ⁺ -CF ₃ COOH).

Example 274

Methyl 4- [3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzo trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and methyl 4- (bromomethyl) benzoate according to the method described in example 258 (b).

MS m / e (ESI) 421.31 (MH ⁺ -CF ₃ COOH).

Example 275

Ethyl 5- [3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] furan-2- trifluoroacetate carboxylate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and ethyl 5- (bromomethyl) furan-2-carboxylate according to the method described in example 258 (b).

MS m / e (ESI) 425.30 (MH ⁺ -CF ₃ COOH).

Example 276

3- (2-Butynyl) -5- [2- (2-nitrophenyl) -2-oxoethyl] -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4 trifluoroacetate -she

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromo-2'-nitroacetophenone according to the method described in example 258 (b).

MS m / e (ESI) 436.28 (MH ⁺ -CF ₃ COOH).

Example 277

4- [2- [3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-yl] acetyl] benzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromo-4'-cyanoacetophenone according to the method described in example 258 (b).

MS m / e (ESI) 416.31 (MH ⁺ -CF ₃ COOH).

Example 278

3- (2-Butynyl) -5- [2- (4-methoxyphenyl) -2-oxoethyl] -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4 trifluoroacetate -she

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromo-4'-methoxyacetophenone according to the method described in example 258 (b).

MS m / e (ESI) 421.32 (MH ⁺ -CF ₃ COOH).

Example 279

3- (2-Butynyl) -5- [2- (2-methoxyphenyl) -2-oxoethyl] -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4 trifluoroacetate -she

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromo-2'-methoxyacetophenone according to the method described in example 258 (b).

MS m / e (ESI) 421.33 (MH ⁺ -CF ₃ COOH).

Example 280

4- [2- [3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-yl] ethyl] benzo trifluoroacetate acid

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and tert-butyl-4- (2-bromoethyl) benzoate according to the method described in example 258 (b).

MS m / e (ESI) 421.33 (MH ⁺ -CF ₃ COOH).

Example 281

3- (2-Butynyl) -2- (piperazin-1-yl) -5- (pyridin-2-ylmethyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one bistrifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2- (chloromethyl) pyridine hydrochloride according to the method described in example 258 (b).

MS m / e (ESI) 364.24 (MH ⁺ -2CF ₃ COOH).

Example 282

3- (2-Butynyl) -2- (piperazin-1-yl) -5- (pyridin-3-ylmethyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one bistrifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 3- (chloromethyl) pyridine hydrochloride according to the method described in example 258 (b).

MS m / e (ESI) 364.30 (MH ⁺ -2CF ₃ COOH).

Example 283

3- (2-Butynyl) -2- (piperazin-1-yl) -5- (pyridin-4-ylmethyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one bistrifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4- (chloromethyl) pyridine hydrochloride according to the method described in example 258 (b).

MS m / e (ESI) 364.26 (MH ⁺ -2CF ₃ COOH).

Example 284

3- (2-Butynyl) -5- [2-oxo-2- (pyridin-2-yl) ethyl] -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] bistrifluoroacetate pyridazin-4-one

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2- (2-bromoacetyl) pyridine hydrobromide according to the method described in example 258 (b).

MS m / e (ESI) 392.27 (MH ⁺ -2CF ₃ COOH).

Example 285

3- (2-Butynyl) -5- [2-oxo-2- (pyridin-3-yl) ethyl] -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] bistrifluoroacetate pyridazin-4-one

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 3- (2-bromoacetyl) pyridine hydrobromide according to the method described in example 258 (b).

MS m / e (ESI) 392.27 (MH ⁺ -2CF ₃ COOH).

Example 286

3- (2-Butynyl) -5- [2-oxo-2- (pyridin-4-yl) ethyl] -2-oxoethyl]] 2- (piperazin-1-yl) -3,5-dihydroimidazo bistrifluoroacetate [ 4,5-d] pyridazin-4-one

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4- (2-bromoacetyl) pyridine hydrobromide according to the method described in example 258 (b).

MS m / e (ESI) 392.28 (MH ⁺ -2CF ₃ COOH).

Example 287

3- (2-Butynyl) -5- (2-methoxypyridin-3-ylmethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 3- (chloromethyl) -2-methoxypyridine according to the method described in example 258 (b).

MS m / e (ESI) 394.30 (MH ⁺ -CF ₃ COOH).

Example 288

Methyl 6- [3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] nicotinate bistrifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and methyl 6- (chloromethyl) nicotinate according to the method described in example 258 (b).

MS m / e (ESI) 422.31 (MH ⁺ -CF ₃ COOH).

Example 289

5- (6-aminopyridin-3-ylmethyl) -3- (2-butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2- (tert-butoxycarbonylamino) -5- (bromomethyl) pyridine according to the method described in example 258 (b).

MS m / e (ESI) 379.31 (MH ⁺ -CF ₃ COOH).

Example 290

4- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] -3-cyano-trifluoroacetate ethoxy-N-methylbenzamide

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4-bromomethyl-3-cyano-5-ethoxy-N-methylbenzamide according to the method described in example 258 (b).

MS m / e (ESI) 489.35 (MH ⁺ -CF ₃ COOH).

Example 291

4- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] -3,5-dicyano trifluoroacetate -N-methylbenzamide

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4-bromomethyl-3,5-dicyano-N-methylbenzamide according to the method described in example 258 (b).

MS m / e (ESI) 470.33 (MH ⁺ -CF ₃ COOH).

Example 292

4- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] -3-cyano-trifluoroacetate fluoro-N-methylbenzamide

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4-bromomethyl-3-cyano-5-fluoro-N-methylbenzamide according to the method described in example 258 (b).

MS m / e (ESI) 463.33 (MH ⁺ -CF ₃ COOH).

Example 293

4- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] -5-cyano- trifluoroacetate 2-ethoxy-N-methylbenzamide

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4-bromomethyl-5-cyano-2-ethoxy-N-methylbenzamide according to the method described in example 258 (b).

MS m / e (ESI) 489.35 (MH ⁺ -CF ₃ COOH).

Example 294

5- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] -2-fluorobenzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 5-bromomethyl-2-fluorobenzonitrile according to the method described in example 258 (b).

MS m / e (ESI) 406.15 (MH ⁺ -CF ₃ COOH).

Example 295

2- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] -5-fluorobenzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromomethyl-5-fluorobenzonitrile according to the method described in example 258 (b).

MS m / e (ESI) 406.16 (MH ⁺ -CF ₃ COOH).

Example 296

4- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] -3-fluorobenzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4-bromomethyl-3-fluorobenzonitrile according to the method described in example 258 (b).

MS m / e (ESI) 406.23 (MH ⁺ -CF ₃ COOH).

Example 297

2- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] -3-fluorobenzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromomethyl-3-fluorobenzonitrile according to the method described in example 258 (b).

MS m / e (ESI) 406.25 (MH ⁺ -CF ₃ COOH).

Example 298

3- (2-Butynyl) -5- (isoquinolin-1-ylmethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 1-bromomethylisoquinoline according to the method described in example 258 (b).

¹ H-NMR (CDCl ₃ )

δ 1.80 (t, J = 2.4 Hz, 3H), 3.46 (m, 4H), 3.68 (m, 4H), 5.17 (q, J = 2.4 Hz, 2H) 6.22 (s, 2H), 7.94 (dd, J = 8.2, 8.0 Hz, 1H), 8.08 (t, J = 8.2 Hz, 1H), 8.21 ( d, J = 8.0 Hz, 1H), 8.24 (d, J = 6.4 Hz, 1H), 8.27 (s, 1H), 8.46 (d, J = 6.4 Hz, 1H), 8.68 (d, J = 8.2 Hz, 1H).

MS m / e (ESI) 414.32 (MH ⁺ -CF ₃ COOH).

Example 299

3- (2-Butynyl) -5- (2-fluoropyridin-3-ylmethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 3- (bromomethyl) -2-fluoropyridine hydrochloride according to the method described in example 258 (b).

MS m / e (ESI) 384.22 (MH ⁺ -CF ₃ COOH).

Example 300

3- (2-Butynyl) -5- (2-fluoropyridin-4-ylmethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4- (bromomethyl) -2-fluoropyridine hydrochloride according to the method described in example 258 (b).

MS m / e (ESI) 384.20 (MH ⁺ -CF ₃ COOH).

Example 301

3- (2-Butynyl) -5- (6-fluoropyridin-2-ylmethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2- (bromomethyl) -6-fluoropyridine hydrochloride according to the method described in example 258 (b).

MS m / e (ESI) 384.22 (MH ⁺ -CF ₃ COOH).

Example 302

2- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzamide trifluoroacetate

0.005 g of potassium carbonate and 0.007 g of 2-bromomethylbenzonitrile are added to a solution containing 0.010 g of tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5- d] pyridazin-2-yl] piperazine-1-carboxylate in 0.5 ml of N, N-dimethylformamide, and the mixture was stirred at room temperature for 20 hours. 1 ml of ethyl acetate and 1 ml of water were added to the reaction solution, and the layers were separated. The organic layer was concentrated and the residue was dissolved in 1.0 ml of methanol. To this solution was added 0.2 ml of an aqueous solution of ammonia and 0.2 ml of a 31% aqueous solution of hydrogen peroxide, and the mixture was stirred at 5 ° C for 20 hours. 1 ml of ethyl acetate and 1 ml of water are added to the reaction solution, and the layers are separated. The organic layer was concentrated and the resulting residue was dissolved in a mixture of 0.5 ml of dichloromethane and 0.5 ml of trifluoroacetic acid. The mixture was stirred for 1 hour and then concentrated. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 0.009 g of the title compound.

MS m / e (ESI) 406.28 (MH ⁺ -CF ₃ COOH).

Example 303

3- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzamide trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 3-bromomethylbenzonitrile according to the method described in example 302.

MS m / e (ESI) 406.30 (MH ⁺ -CF ₃ COOH).

Example 304

4- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzamide trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 4-bromomethylbenzonitrile according to the method described in example 302.

MS m / e (ESI) 406.31 (MH ⁺ -CF ₃ COOH).

Example 305

3- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzoic acid trifluoroacetate

0.005 g of potassium carbonate and 0.008 g of methyl 3- (bromomethyl) benzoate are added to a solution of 0.010 g of tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4 , 5-d] pyridazin-2-yl] piperazin-1-carboxylate in 0.5 ml of N, N-dimethylformamide and the mixture was stirred at room temperature for 20 hours. 1 ml of ethyl acetate and 1 ml of water are added to the reaction mixture, and the layers are separated. The organic layer was concentrated and the residue was dissolved in 1.0 ml of methanol. Add to this solution 0.1 ml of 5 N. aqueous sodium hydroxide solution and the mixture was stirred at room temperature for 20 hours. 1 ml of ethyl acetate and 1 ml of water are added to the reaction solution. The solution was acidified using concentrated hydrochloric acid, and the layers were separated. The organic layer was concentrated and the residue was dissolved in a mixture of 0.5 ml of dichloromethane and 0.5 ml of trifluoroacetic acid. The mixture was stirred for 1 hour and then concentrated. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 0.008 g of the title compound.

MS m / e (ESI) 407.29 (MH ⁺ -CF ₃ COOH).

Example 306

4- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzoic acid trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and methyl 4- (bromomethyl) benzoate according to the method described in example 305.

MS m / e (ESI) 407.30 (MH ⁺ -CF ₃ COOH).

Example 307

5- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] furan-2-carboxylic acid trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and ethyl 5- (bromomethyl) furan-2-carboxylate according to the method described in example 305.

MS m / e (ESI) 397.28 (MH ⁺ -CF ₃ COOH).

Example 308

3-Benzyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) tert-Butyl-4- (1-benzyl-6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazine-1-carboxylate

The title compound was prepared by using tert-butyl-4- (6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazin-1- carboxylate and benzyl bromide according to the method described in example 116 (d).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 3.13-3.18 (m, 4H), 3.50-3.54 (m, 4H), 4.72 (s, 2H), 5.61 (s , 2H), 5.65 (s, 2H), 7.20-7.35 (m, 10H), 8.22 (s, 1H).

(b) 3-Benzyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by treating tert-butyl-4- (1-benzyl-6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazine-1-carboxylate according to the method described in example 117.

¹ H-NMR (CD ₃ OD)

δ 3.31-3.37 (m, 4H), 3.40-3.46 (m, 4H), 5.68 (s, 2H), 7.22-7.36 (m, 5H), 8 25 (s, 1H).

MS m / e (ESI), 311.24 (MH ⁺ -CF ₃ COOH).

Example 309

3-Benzyl-5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) tert-Butyl-4- (1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazine-1-carboxylate

The title compound was prepared by using 3-benzyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate according to the method described in Example 258 (a )

¹ H-NMR (CDCl ₃ )

δ 1.47 (s, 9H), 3.12-3.16 (m, 4H), 3.47-3.52 (m, 4H), 5.58 (s, 2H), 7.20-7 34 (m, 5H), 8.20 (s, 1H), 10.04 (br s, 1H).

(b) 3-Benzyl-5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- (1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazin-1- carboxylate and methyl iodide according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 3.29-3.35 (m, 4H), 3.36-3.41 (m, 4H), 3.83 (s, 3H), 5.68 (s, 2H), 7.21-7 34 (m, 5H); 8.20 (s, 1H).

MS m / e (ESI) 325.01 (MH ⁺ -CF ₃ COOH).

Example 310

3-Benzyl-5- (2-oxo-2-phenylethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and 2-bromoacetophenone according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 3.31-3.36 (m, 4H), 3.44-3.49 (m, 4H), 5.69 (s, 2H), 5.77 (s, 2H), 7.22-7 52 (m, 8H), 8.06 (d, J = 9.3 Hz, 2H), 8.32 (s, 1H).

MS m / e (ESI) 429.39 (MH ⁺ -CF ₃ COOH).

Example 311

3-Benzyl-5- (2-phenylethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and (2-bromoethyl) benzene according to the method described in example 258 (b).

¹ H-NMR (CDCl ₃ )

δ 3.11 (t, J = 8.1 Hz, 2H), 3.24-3.29 (m, 4H), 3.37-3.42 (m, 4H), 4.46 (t, J = 8.1 Hz, 2H), 5.58 (s, 2H), 7.09-7.34 (m, 10H), 8.20 (s, 1H).

MS m / e (ESI), 415.54 (MH ⁺ -CF ₃ COOH).

Example 312

3-Benzyl-5- (2-phenoxyethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and 2-bromoethylphenyl ether according to the method described in example 258 (b).

¹ H-NMR (CDCl ₃ )

δ 3.21-3.24 (m, 4H), 3.37-3.42 (m, 4H), 4.37 (t, J = 5.8 Hz, 2H), 4.64 (t, J = 5.8 Hz, 2H), 5.58 (s, 2H), 6.86-6.94 (m, 3H), 7.07-7.34 (m, 7H), 8.21 (s, 1H).

MS m / e (ESI) 431.57 (MH ⁺ -CF ₃ COOH).

Example 313

3-benzyl-2- (piperazin-1-yl) -5- (2-propynyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and 3-bromo-1-propine according to the method described in example 258 (b).

MS m / e (ESI) 349.31 (MH ⁺ -CF ₃ COOH).

Example 314

[3-Benzyl-4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-yl] acetonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and bromoacetonitrile according to the method described in example 258 (b).

MS m / e (ESI) 350.30 (MH ⁺ -CF ₃ COOH).

Example 315

3-Benzyl-5- (2-hydroxyethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and 2-bromoethanol according to the method described in example 258 (b).

MS m / e (ESI) 355.32 (MH ⁺ -CF ₃ COOH).

Example 316

3-Benzyl-5- (2-methoxyethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and bromoethyl methyl ether according to the method described in example 258 (b).

MS m / e (ESI) 369.35 (MH ⁺ -CF ₃ COOH).

Example 317

Ethyl [3-benzyl-4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-yl] acetate trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and ethyl bromoacetate according to the method described in example 258 (b).

MS m / e (ESI) 397.33 (MH ⁺ -CF ₃ COOH).

Example 318

3-Benzyl-5- [2- (3-methoxyphenyl) -2-oxoethyl] -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and 2-bromo-3'-methoxyacetophenone according to the method described in example 258 (b).

MS m / e (ESI) 459.34 (MH ⁺ -CF ₃ COOH).

Example 319

Trifluoroacetate 2- [3-benzyl-4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzonitrile

The title compound was prepared by using tert-butyl-4- [1-benzyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin-1- carboxylate and 2-bromomethylbenzonitrile according to the method described in example 258 (b).

MS m / e (ESI) 326.33 (MH ⁺ -CF ₃ COOH).

Example 320

5-methyl-2- (piperazin-1-yl) -3- (2-propynyl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- (6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazin-1- carboxylate and 3-bromo-1-propine according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 2.99 (t, J = 3.3 Hz, 1H), 3.45-3.49 (m, 4H), 3.65-3.69 (m, 4H), 3.83 (s, 3H ), 5.75 (d, J = 3.3 Hz, 2H), 8.20 (s, 1H).

MS m / e (ESI) 273.1 (MH ⁺ -CF ₃ COOH).

Example 321

3- (2-Butenyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- (6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazin-1- carboxylate and 1-bromo-2-butene according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 1.69 and 1.84 (dd, J = 6.3, 1.3 Hz, and dd, J = 6.3, 1.3 Hz, 3H), 3.43-3.48 (m, 4H ), 3.54-3.58 (m, 4H), 3.82 and 3.84 (s, 3H), 4.94 and 5.07 (d, J = 6.5 Hz, and d, J = 6.5 Hz, 2H), 5.63-5.80 and 6.11-6.20 (m, 2H), 8.19 and 8.22 (s, 1H).

MS m / e (ESI), 289.2 (MH ⁺ -CF ₃ COOH).

Example 322

5-methyl-3- (2-pentenyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- (6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazin-1- carboxylate and 1-bromo-2-pentene according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 0.97 and 1.08 (t, J = 7.7 Hz, and t, J = 7.7 Hz, 3H), 2.04-2.27 (m, 2H), 3.42-3, 46 (m, 4H), 3.54-3.58 (m, 4H), 3.81 and 3.84 (s, 3H), 4.91-4.96 (m, 2H), 5.59- 5.81 and 6.14-6.22 (m, 2H), 8.19 and 8.22 (s, 1H)

MS m / e (ESI) 303.25 (MH ⁺ -CF ₃ COOH).

Example 323

5-methyl-3- (3-methyl-2-butenyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- (6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazin-1- carboxylate and 1-bromo-3-methyl-2-butene according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 1.75 (s, 3H), 1.83 (s, 3H), 3.43-3.47 (m, 4H), 3.52-3.57 (m, 4H), 3.84 (s , 3H), 5.00 (d, J = 6.8 Hz, 2H), 5.40-5.45 (m, 1H), 8.17 (s, 1H).

MS m / e (ESI) 303.27 (MH ⁺ -CF ₃ COOH).

Example 324

3-Cyclopropylmethyl-5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- (6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperazin-1- carboxylate and cyclopropylmethyl bromide according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 0.44-0.55 (m, 4H), 0.81-0.85 (m, 1H), 3.42-3.46 (m, 4H), 3.54-3.58 (m, 4H), 3.83 (s, 3H), 4.39 (d, J = 6.6 Hz, 2H), 8.21 (s, 1H).

MS m / e (ESI) 289.25 (MH ⁺ -CF ₃ COOH).

Example 325

5- [2- (2-aminophenyl) -2-oxoethyl] -3- (2-butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4 bistrifluoroacetate -she

(a) tert-Butyl-4- [1- (2-butynyl) -6- [2- (2-nitrophenyl) -2-oxoethyl] -7-oxo-6,7-dihydro-1H-imidazo [4, 5-d] pyridazin-2-yl] piperazin-1-carboxylate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 2-bromo-2'-nitroacetophenone according to the method described in example 258 (b).

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.83 (t, J = 2.3 Hz, 3H), 3.37-3.44 (m, 4H), 3.50-3.55 (m, 4H ), 5.04 (q, J = 2.3 Hz, 2H), 5.44 (s, 2H), 7.62 (m, 1H), 7.71-7.74 (m, 2H), 8 13 (d, J = 7.9 Hz, 1H); 8.21 (s, 1H).

(b) 5- [2- (2-aminophenyl) -2-oxoethyl] -3- (2-butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] bistrifluoroacetate pyridazin-4-one

2 ml of water, 0.070 g of iron and 0.007 g of ammonium chloride are added to a solution of 0.058 g of tert-butyl-4- [1- (2-butynyl) -6- [2- (2-nitrophenyl) -2-oxoethyl] -7- oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate in 5 ml of ethanol and the mixture was refluxed for three hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 4 ml of dichloromethane and 4 ml of trifluoroacetic acid was added to the solution. After stirring the mixture for two hours, the solution was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 0.051 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.82 (t, J = 2.3 Hz, 3H), 3.45-3.50 (m, 4H), 3.68-3.72 (m, 4H), 5.16 (q, J = 2.3 Hz, 2H), 5.68 (s, 2H), 6.56 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 8.25 (s, 1H).

MS m / e (ESI) 406.22 (MH ⁺ -CF ₃ COOH).

Example 326

3- (2-Butynyl) -5,7-dimethyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) tert-Butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4- (1-hydroxyethyl) -1H-imidazol-2-yl] piperazine-1-carboxylate

Add 0.5 ml of a 0.3 M tetrahydrofuran solution of methylmagnesium bromide in 3 ml of a tetrahydrofuran solution of 0.050 g of tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl] piperazine-1-carboxylate at a temperature of -70ºC in a nitrogen atmosphere and allow the mixture to warm to room temperature. 10 ml of a 5% aqueous solution of ammonium chloride are added to this solution, and the mixture is extracted with 30 ml of ethyl acetate. The organic layer was washed successively with 10 ml of water and 10 ml of a saturated solution of sodium chloride, then dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.049 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1: 1).

¹ H-NMR (CDCl ₃ )

δ 1.37 (t, J = 7.1 Hz, 3H), 1.47 (d, J = 6.9 Hz, 3H), 1.48 (s, 9H), 1.81 (t, J = 2.3 Hz, 3H), 3.17-3.22 (m, 4H), 3.55-3.59 (m, 4H), 3.84 (d, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.78 (q, J = 2, 3 Hz, 2H), 5.12 (q, J = 6.9 Hz, 1H).

(b) tert-Butyl-4- [4-acetyl-1- (2-butynyl) -5-ethoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4- (1-hydroxyethyl) -1H-imidazol-2-yl] piperazine-1-carboxylate according to the method described in example 115 (g).

¹ H-NMR (CDCl ₃ )

δ 1.38 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 1.79 (t, J = 2.3 Hz, 3H), 2.53 (s, 3H) , 3.14-3.18 (m, 4H), 3.56-3.60 (m, 4H), 4.38 (q, J = 7.1 Hz, 2H), 4.77 (q, J = 2.3 Hz, 2H).

(c) 3- (2-Butynyl) -5,7-dimethyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

Add 0.15 ml of methylhydrazine to a solution of 0.019 g of tert-butyl [4-acetyl-1- (2-butynyl) -5-ethoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate in 3 ml of ethanol and the mixture is heated at 110ºC for 25 hours. The solution was concentrated under reduced pressure. The residue was dissolved in 0.5 ml of dichloromethane and 0.5 ml of trifluoroacetic acid was added to the solution. The solution was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.017 g of the title compound.

MS m / e (ESI) 301.33 (MH ⁺ -CF ₃ COOH).

Example 327

3- (2-Butynyl) -7-phenyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) tert-Butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4- (1-hydroxyphenylmethyl) -1H-imidazol-2-yl] piperazine-1-carboxylate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl] piperazine-1-carboxylate and phenylmagnesium bromide according to the method, described in example 326 (a).

¹ H-NMR (CDCl ₃ )

δ 1.33 (t, J = 7.3 Hz, 3H), 1.48 (s, 9H), 1.81 (t, J = 2.2 Hz, 3H), 3.16-3.27 ( m, 4H), 3.55-3.59 (m, 4H), 4.24-4.34 (m, 2H), 4.39 (d, J = 8.3 Hz, 1H), 4.78 (q, J = 2.2 Hz, 2H), 6.09 (d, J = 8.3 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.30 (t , J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H).

(b) tert-Butyl-4- [4-benzoyl-1- (2-butynyl) -5-ethoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4- (1-hydroxyphenylmethyl) -1H-imidazol-2-yl] piperazine-1-carboxylate according to the method described in example 115 (g).

¹ H-NMR (CDCl ₃ )

δ 0.92 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 1.83 (t, J = 2.3 Hz, 3H), 3.22-3.28 ( m, 4H), 3.57-3.62 (m, 4H), 4.03 (q, J = 7.1 Hz, 2H), 4.88 (q, J = 2.3 Hz, 2H), 7.43 (t, J = 8.1 Hz, 2H), 7.55 (t, J = 8.1 Hz, 1H), 7.92 (d, J = 8, l Hz, 2H).

(c) tert-Butyl-4- [1- (2-butynyl) -7-oxo-4-phenyl-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin- 1-carboxylate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4- (1-hydroxyphenylmethyl) -1H-imidazol-2-yl] piperazine-1-carboxylate and hydrazine according to the method described in example 115 (h).

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.83 (t, J = 2.3 Hz, 3H), 3.44-3.48 (m, 4H), 3.63-3.67 (m, 4H ), 5.15 (q, J = 2.3 Hz, 2H), 7.40-7.50 (m, 3H), 8.34 (d, J = 8.1 Hz, 2H), 10.70 (s, 1H).

(d) 3- (2-Butynyl) -7-phenyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-4-phenyl-6,7-dihydro-1H-imidazo [4,5-d] pyridazin- 2-yl] piperazin-1-carboxylate according to the method described in example 115 (i).

MS m / e (ESI) 349.30 (MH ⁺ -CF ₃ COOH).

Example 328

3- (2-Butynyl) -5-methyl-7-phenyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-4-phenyl-6,7-dihydro-1H-imidazo [4,5-d] pyridazin- 2-yl] piperazin-1-carboxylate and methyl iodide according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 1.83 (t, J = 2.4 Hz, 3H), 3.47-3.51 (m, 4H), 3.71-3.75 (m, 4H), 3.92 (s, 3H ), 5.22 (q, J = 2.4 Hz, 2H), 7.43-7.48 (m, 3H), 8.35 (d, J = 8.1 Hz, 2H).

MS m / e (ESI) 363.31 (MH ⁺ -CF ₃ COOH).

Example 329

[3- (2-Butynyl) -4-oxo-7-phenyl-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-yl] acetic acid trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-4-phenyl-6,7-dihydro-1H-imidazo [4,5-d] pyridazin- 2-yl] piperazin-1-carboxylate and tert-butyl bromoacetate according to the method described in example 258 (b).

MS m / e (ESI) 407.29 (MH ⁺ -CF ₃ COOH).

Example 330

2- [3- (2-Butynyl) -4-oxo-7-phenyl-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-4-phenyl-6,7-dihydro-1H-imidazo [4,5-d] pyridazin- 2-yl] piperazin-1-carboxylate and 2-bromomethylbenzonitrile according to the method described in example 258 (b).

MS m / e (ESI) 464.33 (MH ⁺ -CF ₃ COOH).

Example 331

3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -7-trifluoromethyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) tert-Butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4- (2,2,2-trifluoro-1-hydroxyethyl) -1H-imidazol-2-yl] piperazin-1- carboxylate

Add 0.065 g of zinc and a solution of 0.200 g of trifluoromethyl iodide in 2 ml of N, N-dimethylformamide to a solution of 0.155 g of tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4-formyl-1H-imidazole-2- il] piperazine-1-carboxylate in 3 ml of N, N-dimethylformamide in a nitrogen atmosphere and the mixture was stirred by sonication for 30 minutes. To the mixture was added 30 ml of ethyl acetate and 30 ml of a 5% solution of ammonium chloride. The organic layer was washed twice with water (20 ml) and then 20 ml of a saturated solution of sodium chloride, and dried over magnesium sulfate. The organic liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.013 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1: 9).

¹ H-NMR (CDCl ₃ )

δ 1.39 (t, J = 6.9 Hz, 3H), 1.48 (s, 9H), 1.83 (t, J = 2.4 Hz, 3H), 3.15-3.26 ( m, 4H), 3.55-3.60 (m, 4H), 4.34 (qs, J = 10.2, 6.9 Hz, 2H), 4.53-4.64 (br.s , 1H); 4.83 (q q, J = 17.6, 2.4 Hz, 2H); 5.39-5.47 (br s, 1H).

(b) 3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -7-trifluoromethyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

Add 0.060 g of Dess-Martin reagent to a solution of 0.013 g of tert-butyl-4- [1- (2-butynyl) -5-ethoxycarbonyl-4- (2,2,2-trifluoro-1-hydroxyethyl) -1H-imidazole- 2-yl] piperazine-1-carboxylate in 4 ml of dichloromethane and the mixture was stirred at room temperature for 15 hours. 5 ml of dichloromethane, 10 ml of a saturated aqueous sodium bicarbonate solution and 0.100 g of sodium hydrosulfite are added to this solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 4 ml of ethanol and 0.2 ml of methylhydrazine was added to the solution. The mixture is heated at 110ºC for 20 hours. The solution was concentrated under reduced pressure. The residue was dissolved in 0.5 ml of dichloromethane and 0.5 ml of trifluoroacetic acid was added to the solution. The solution was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 0.008 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.83 (t, J = 2.3 Hz, 3H), 3.45-3.49 (m, 4H), 3.71-3.75 (m, 4H), 3.87 (s, 3H ), 5.18 (q, J = 2.3 Hz, 2H).

MS m / e (ESI) 355.16 (MH ⁺ -CF ₃ COOH).

Example 332

1- (2-Butynyl) -6-methyl-7-oxo-2- (piperazin-1-yl) -6,7-dihydroimidazo [4,5-d] pyridazin-4-carboxamide trifluoroacetate

(a) tert-Butyl-4- [1- (2-butynyl) -4- (cyanohydroxymethyl) -5-methoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

Add 0.200 g of sodium cyanide and 0.010 ml of acetic acid to a solution of tert-butyl-4- [1- (2-butynyl) -5-methoxycarbonyl-4-formyl-1H-imidazol-2-yl] piperazine-1-carboxylate in 15 ml of acetonitrile and the mixture was stirred at room temperature for 16 hours. 100 ml of ethyl acetate are added to the solution and the mixture is washed twice with water (50 ml) and then 50 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.274 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2: 3).

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.83 (t, J = 2.5 Hz, 3H), 3.19-3.23 (m, 4H), 3.56-3.60 (m, 4H ), 3.95 (s, 3H), 4.68 (d, J = 9.0 Hz, 1H), 4.82 (q, J = 2.5 Hz, 2H), 5.72 (d, J = 9.0 Hz, 1H).

(b) tert-Butyl-4- [1- (2-butynyl) -4- (carbamoylhydroxymethyl) -5-methoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

3.2 ml of a 30% aqueous solution of hydrogen peroxide and 3.2 ml of a 28% aqueous solution of ammonia are added to a solution of 0.274 g of tert-butyl-4- [1- (2-butynyl) -4- (cyanohydroxymethyl) -5-methoxycarbonyl- 1H-imidazol-2-yl] piperazine-1-carboxylate in 8 ml of methanol at 5 ° C and the mixture was stirred for 15 hours. To this solution was added 100 ml of a saturated solution of sodium hydrogen sulfite and the mixture was extracted twice with 100 ml of ethyl acetate. Organic layers are combined. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.039 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1: 9).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.83 (t, J = 2.5 Hz, 3H), 3.13-3.25 (m, 4H), 3.54-3.57 (m, 4H ), 3.91 (s, 3H), 4.33-4.37 (br s, 1H), 4.77 (q, J = 2.5 Hz, 2H), 5.54 (s, 1H) 5.63 (s, 1H); 6.82 (s, 1H).

(c) tert-Butyl-4- [4-aminooxalyl-1- (2-butynyl) -5-methoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

0.051 ml of triethylamine and a solution of 0.058 g of a complex of sulfur trioxide-pyridine in 1 ml of dimethyl sulfoxide are added to a solution of 0.038 g of tert-butyl-4- [1- (2-butynyl) -4- (carbamoylhydroxymethyl) -5-methoxycarbonyl-1H-imidazole- 2-yl] piperazine-1-carboxylate in 2 ml of dichloromethane at 0 ° C and the mixture was stirred at room temperature for 15 hours. Then, 0.102 ml of triethylamine and a solution of 0.116 g of a complex of sulfur trioxide-pyridine in 1 ml of dimethyl sulfoxide are added and the mixture is stirred at room temperature for 8 hours. 50 ml of ethyl acetate was added to the solution, and the organic layer was washed successively with an aqueous solution of 1% sulfuric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and saturated sodium chloride solution (20 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.021 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2: 1).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.82 (t, J = 2.5 Hz, 3H), 3.19-3.23 (m, 4H), 3.56-3.59 (m, 4H ), 3.84 (s, 3H), 4.84 (q, J = 2.5 Hz, 2H), 5.62 (br s, 1H), 7.02 (br s, 1H).

(d) tert-Butyl-4- [1- (2-butynyl) -4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-1H-dihydroimidazo [4,5-d] pyridazin-2- sludge] piperazine-1-carboxylate

The title compound was prepared by using tert-butyl-4- [4-aminooxalyl-1- (2-butynyl) -5-methoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate according to the method described in Example 115 (h).

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.84 (t, J = 2.3 Hz, 3H), 3.46-3.50 (m, 4H), 3.63-3.66 (m, 4H ), 3.99 (s, 3H), 5.12 (q, J = 2.3 Hz, 2H), 6.16 (s, 1H), 8.85 (s, 1H).

(e) 1- (2-Butynyl) -6-methyl-7-oxo-2- (piperazin-1-yl) -6,7-dihydroimidazo [4,5-d] pyridazin-4-carboxamide trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-1H-dihydroimidazo [4,5- d] pyridazin-2-yl] piperazine-1-carboxylate according to the method described in example 115 (i).

MS m / e (ESI) 330.18 (MH ⁺ -CF ₃ COOH).

Example 333

1- (2-Butynyl) -6-methyl-7-oxo-2- (piperazin-1-yl) -6,7-dihydroimidazo [4,5-d] pyridazin-4-carbonitrile trifluoroacetate

0.030 ml of triethylamine and 0.015 ml of phosphorus oxychloride are added to a solution of 0.015 g of tert-butyl-4- [1- (2-butynyl) -4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-1H-dihydroimidazo [ 4,5-d] pyridazin-2-yl] piperazin-1-carboxylate in 1 ml of dichloromethane and the mixture was stirred at room temperature for 15 hours. 1 ml of dichloromethane and 1 ml of trifluoroacetic acid are added to this solution. After one hour, the solution was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.001 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.83 (t, J = 2.3 Hz, 3H), 3.45-3.49 (m, 4H), 3.74-3.78 (m, 4H), 3.88 (s, 3H ), 5.18 (q, J = 2.3 Hz, 2H).

MS m / e (ESI) 312.25 (MH ⁺ -CF ₃ COOH).

Example 334

3- (2-Butynyl) -7-dimethylamino-5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

( a) 1-Benzyl-7-chloro-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one

0.604 g of potassium carbonate and 0.297 ml of methyl iodide are added to a solution of 1.035 g of 1-benzyl-7-chloro-1,5-dihydroimidazo [4,5-d] pyridazin-4-one in 30 ml of N, N-dimethylformamide (JA Carbon, Journal of the American Chemical Society, 80, p. 6083, 1958) and the mixture was stirred at room temperature for 15 hours. 300 ml of ethyl acetate and 100 ml of water are added to the solution, and the organic layer is washed twice with water (100 ml) and then 100 ml of a saturated solution of sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.280 g of the title compound was obtained from the fraction eluted with ethyl acetate.

¹ H-NMR (CDCl ₃ )

δ 3.86 (s, 3H), 5.64 (s, 2H), 7.11-7.16 (m, 2H), 7.35-7.43 (m, 3H), 7.90 (s , 1H).

(b) 1-Benzyl-7-dimethylamino-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one

Add 2 ml of an aqueous solution of 50% dimethylamine to a solution of 0.138 g of 1-benzyl-7-chloro-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one in 2 ml of ethanol and the mixture is heated at 130 ° C within 72 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.139 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:19).

¹ H-NMR (CDCl ₃ )

δ 2.73 (s, 6H), 3.79 (s, 3H), 5.59 (s, 2H), 7.12-7.16 (m, 2H), 7.30-7.39 (m , 3H); 7.79 (s, 1H).

(c) 1-Benzyl-2-chloro-7-dimethylamino-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one

1.15 ml of a 1 M solution of dibutyl magnesium in tetrahydrofuran was added to a solution of 0.320 ml of diisopropylamine in 2 ml of tetrahydrofuran at room temperature under a nitrogen atmosphere, and the mixture was stirred for 8 hours. This solution was added to a solution of 0.162 g of 1-benzyl-7-dimethylamino-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one in 4 ml of tetrahydrofuran at room temperature under a nitrogen atmosphere and the mixture was stirred at room temperature for 15 hours. Then, a solution of 0.540 g of hexachloroethane in 5 ml of tetrahydrofuran is added dropwise to this solution. After the mixture was stirred for 4 hours, 30 ml of a 5% aqueous solution of ammonium chloride was added thereto. The mixture was extracted with ethyl acetate (100 ml). The organic layer was washed successively with water (30 ml) and 30 ml of a saturated solution of sodium chloride and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.094 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2: 1).

¹ H-NMR (CDCl ₃ )

δ 2.68 (s, 6H), 3.78 (s, 3H), 5.60 (s, 2H), 7.05-7.08 (m, 2H), 7.29-7.37 (m , 3H).

(d) tert-Butyl-4- [1-benzyl-7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin- 1-carboxylate

The title compound was prepared by using 1-benzyl-2-chloro-7-dimethylamino-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one according to the method described in example 116 ( c)

¹ H-NMR (CDCl ₃ )

δ 1.47 (s, 9H), 2.68 (s, 6H), 3.19-3.22 (m, 4H), 3.41-3.46 (m, 4H), 3.76 (s , 3H), 5.40 (s, 2H), 6.88 (m, 2H), 7.20-7.25 (m, 3H).

(e) tert-Butyl-4- [7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate

A solution of 0.117 g of tert-butyl-4- [1-benzyl-7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine is added -1-carboxylate in 5 ml of tetrahydrofuran to 15 ml of liquid ammonia and 0.009 g of lithium are added to the mixture under reflux. 1 ml of a 5% aqueous solution of ammonium chloride was added to the solution, and the solvent was evaporated. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.007 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.48 (s, 9H), 3.11 (s, 6H), 3.55-3.58 (m, 8H), 3.69 (s, 3H).

(f) 3- (2-Butynyl) -7-dimethylamino-5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazine-1-carboxylate and 1-bromo-2-butine according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 1.80 (t, J = 2.3 Hz, 3H), 2.75 (s, 6H), 3.44-3.48 (m, 4H), 3.62-3.65 (m, 4H ), 3.68 (s, 3H), 5.16 (q, J = 2.3 Hz, 2H).

MS m / e (ESI) 330.16 (MH ⁺ -CF ₃ COOH).

Example 335

3- (2-Butynyl) -5-methyl-2- (piperidin-4-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) 5-Methyl-2- (piperidin-4-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

2.71 g of iron (III) chloride was added to a solution of 0.292 g of 4,5-diamino-2-methyl-2H-pyridazin-3-one in 16 ml of ethanol [CAS No. 4725-76-2] (Martine Beljean-Leymarie, Michel Pays and Jean-Claude Richer, Canadian Journal of Chemistry 61, p. 2563, 1983) and 0.426 g of tert-butyl-4-formylpiperidine-1-carboxylate and the mixture is heated with reflux for 6 hours. The reaction solution was cooled to room temperature. The solution was filtered and concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to obtain 0.061 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 2.06-2.17 (m, 2H), 2.28-2.35 (m, 2H), 3.15-3.24 (m, 2H), 3.29-3.35 (m, 1H), 3.50-3.56 (m, 2H), 3.85 (s, 3H), 8.28 (s, 1H).

(b) tert-Butyl-4- (6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperidine-1-carboxylate

The title compound was prepared by using 5-methyl-2- (piperidin-4-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate according to the method described in Example 258 (a )

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 2.00-2.16 (m, 4H), 2.85-2.99 (br s, 2H), 3.23 (t, J = 11.9, 4.0 Hz, 1H), 3.95 (s, 3H), 4.11-4.40 (br s, 2H), 8.39 (s, 1H), 13.90 (s, 1H).

(c) tert-Butyl-4- [1- (2-butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperidin- 1-carboxylate

The title compound was prepared by using tert-butyl-4- (6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl) piperidin-1- carboxylate according to the method described in example 119 (d).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.81 (t, J = 2.3 Hz, 3H), 1.93-2.00 (m, 4H), 2.85-2.96 (br s , 2H), 3.14 (q, J = 7.9 Hz, 1H), 3.85 (s, 3H), 4.16-4.37 (br s, 2H), 5.39 (q, J = 2.3 Hz, 2H), 8.24 (s, 1H).

(d) 3- (2-Butynyl) -5-methyl-2- (piperidin-4-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin- 2-yl] piperidin-1-carboxylate according to the method described in example 115 (i).

¹ H-NMR (CD ₃ OD)

δ 1.80 (t, J = 2.3 Hz, 3H), 2.10-2.11 (m, 2H), 2.25-2.32 (m, 2H), 3.18-3.41 (m, 3H), 3.56-3.61 (m, 2H), 3.83 (s, 3H), 5.47 (t, J = 2.3 Hz, 2H), 8.27 (s, 1H).

MS m / e (ESI), 286.27 (MH ⁺ -CF ₃ COOH).

Example 336

3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

(a) 3- (2-Butynyl) -4-chloro-3H-imidazo [4,5-c] pyridine

2.0 g of 4-chloro-1H-imidazo [4,5-c] pyridine, 1.37 ml of 1-bromo-2-butine and 1.98 g of potassium carbonate in 15 ml of N, N-dimethylformamide are suspended and the suspension is stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 1.79 g of the mixture (1: 1) consisting of the title compound and the compound alkylated at position-1 were obtained from the fraction eluted with hexane-ethyl acetate (1: 2).

(b) 3- (2-Butynyl) -2,4-dichloro-3H-imidazo [4,5-c] pyridine

A solution of lithium diisopropylamide in 2.22 ml of tetrahydrofuran to 5 ml of a tetrahydrofuran solution of 490 mg of 3- (2-butynyl) -4-chloro-3H-imidazo [4,5-c] pyridine is added dropwise in a bath with a mixture of dry ice-methanol and the mixture is stirred at a temperature below -66ºC for 20 minutes. The resulting reaction mixture was added dropwise to a solution of 1.13 g of hexachloroethane in 2 ml of tetrahydrofuran, while controlling that the temperature of the mixture was -63 ° C or lower. The mixture was stirred for 1 hour and 40 minutes in the same bath, and then a saturated aqueous solution of ammonium chloride was added to the solution. The resulting mixture was extracted twice with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. Then, the resulting residue is purified by silica gel column chromatography. Thus, 120 mg of a brown oily material was obtained from the fraction eluted with hexane-ethyl acetate (2: 1).

¹ H-NMR (DMSO-d ₆ )

δ 1.78 (s, 3H), 5.29 (s, 2H), 7.70 (d, J = 5.6 Hz, 1H), 8.21 (d, J = 5.6 Hz, 1H) .

(c) tert-Butyl-4- [3- (2-butynyl) -4-chloro-3H-imidazo [4,5-c] pyridin-2-yl] piperazine-1-carboxylate

211 mg of tert-butyl-3- (2-butynyl) -2,4-dichloro-3H-imidazo [4,5-c] pyridine, 197 mg of piperazine-1-carboxylate and 222 mg of sodium bicarbonate are dissolved in ethanol, the mixture is stirred at 80ºC for 30 minutes and then at room temperature for three hours and 20 minutes. The reaction solution was diluted with ethyl acetate and the solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 244 mg of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3: 1).

¹ H-NMR (CDCl ₃ )

δ 1.52 (s, 9H), 1.87 (s, 3H), 3.47-3.49 (m, 4H), 3.65-3.68 (m, 4H), 4.94 (s , 2H), 7.41 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 5.2 Hz, 1H).

(d) 3- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

98 mg of sodium acetate is dissolved in 2 ml of dimethyl sulfoxide containing 0.3 mmol of tert-butyl-4- [3- (2-butynyl) -4-chloro-3H-imidazo [4,5-c] pyridin-2-yl] piperazine-1-carboxylate, and the mixture was stirred at 120 ° C for 4 hours. Then, 100 mg of potassium carbonate and 1 ml of methyl iodide are added to the reaction solution. The mixture was stirred at room temperature. The reaction solution was diluted with ethyl acetate and the solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 5 mg of the product obtained from the fraction eluted with methanol-ethyl acetate (1:10) was dissolved in 0.5 ml of trifluoroacetic acid, and the mixture was concentrated. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.55 mg of the title compound.

MS m / e (ESI) 286 (MH ⁺ -CF ₃ COOH).

Example 337

3-benzyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

(a) Allyl- (3-nitropyridin-4-yl) amine

40 ml of allylamine is added to a solution of 18.0 g of 4-ethoxy-3-nitropyridine hydrochloride in 400 ml of ethanol, and the mixture is heated under reflux for 8 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 13.6 g of the title compound were obtained from the fraction eluted with ethyl acetate-hexane (1: 1).

¹ H-NMR (CDCl ₃ )

δ 4.00 (m, 2H), 5.29-5.35 (m, 2H), 5.87-5.98 (m, 1H), 6.63 (d, J = 6.5 Hz, 1H ), 8.30 (d, J = 6.5 Hz, 1H), 8.31 (br s, 1H), 9.23 (s, 1H).

(b) N * -4 * -allyl-2-chloropyridin-3,4-diamine

55 ml of 35% hydrochloric acid are added to 3.02 g of allyl- (3-nitropyridin-4-yl) amine and the mixture is heated to 90 ° C. 19.1 g of tin chloride are added to this solution and the mixture is kept at 90 ° C for 30 minutes. The reaction solution was cooled in an ice water bath and then 250 ml of ice water was added to the solution. The reaction solution was concentrated under reduced pressure and then 250 ml of methanol saturated with ammonia were added to the solution. The mixture was stirred for 20 hours. 750 ml of ethyl acetate are added to the solution and the mixture is filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.88 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1: 1).

¹ H-NMR (CDCl ₃ )

δ 3.29-3.58 (br s, 2H), 3.84 (d, J = 6.3 Hz, 2H), 4.26-4.37 (br s, 1H), 5.24 (d, J = 11.0 Hz, 1H), 5.29 (d, J = 16.0 Hz, 1H), 5.85-5.98 (ddt, J = 16.0, 11.0, 6 5 Hz, 1H), 6.43 (d, J = 6.5 Hz, 1H), 7.66 (d, J = 6.5 Hz, 1H).

(c) 1-Allyl-4-chloro-1,3-dihydroimidazo [4,5-c] pyridin-2-one

A solution of 4.46 g of N, N'-disuccinimidyl carbonate in 400 ml of acetonitrile was added to a solution containing 2.88 g of N * -4 * -allyl-2-chloropyridin-3,4-diamine in acetonitrile, and the mixture was heated under reflux. for 70 hours. The solution was concentrated under reduced pressure and the residue was dissolved in a mixture of 500 ml of ethyl acetate and 300 ml of water. The organic layer is washed twice with 1 N. hydrochloric acid (100 ml) and then a saturated solution of sodium chloride (100 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.30 g of the title compound was obtained from the fraction eluted with ethyl acetate-dichloromethane (1: 1).

¹ H-NMR (CDCl ₃ )

δ 4.51 (d, J = 5.7 Hz, 1H), 5.25, (d, J = 16.0 Hz, 1H), 5.30 (d, J = 10.9 Hz, 1H), 5.85-5.95 (ddt, J = 16.0, 10.9, 5.7 Hz, 1H), 6.91 (d, J = 6.9 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H), 8.99 (br s, 1H).

(d) 1-Allyl-3-benzyl-4-chloro-1,3-dihydroimidazo [4,5-c] pyridin-2-one

0.76 g of potassium carbonate and 0.94 g of benzyl bromide are added to a solution of 1.05 g of 1-allyl-4-chloro-1,3-dihydroimidazo [4,5-c] pyridin-2-one in 50 ml of N, N β-dimethylformamide and the mixture was stirred at room temperature for 14 hours. 300 ml of water and 300 ml of ethyl acetate are added to this solution, the organic layer is washed three times with water (100 ml) and then 100 ml of a saturated solution of sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 1.57 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 4.56 (d, J = 5.7 Hz, 1H), 5.23 (d, J = 16.0 Hz, 1H), 5.30 (d, J = 10.9 Hz, 1H), 5 44 (s, 2H), 5.85-5.95 (ddt, J = 16.0, 10.9, 5.7 Hz, 1H), 6.91 (d, J = 6.9 Hz, 1H ), 7.25-7.34 (m, 5H), 8.08 (d, J = 6.9 Hz, 1H), 8.99 (br s, 1H).

(e) 3-Benzyl-4-chloro-1,3-dihydroimidazo [4,5-c] pyridin-2-one

1.5 ml of water, 1.06 g of 4-methylmorpholine-N-oxide, 3 ml of an aqueous solution (2%) of osmic acid and 6 ml of an aqueous solution of 1.94 g of sodium periodate are added to a solution of 0.75 g of 1-allyl- 3-benzyl-4-chloro-1,3-dihydroimidazo [4,5-c] pyridin-2-one in 15 ml of 1,4-dioxane and the mixture is heated at 60 ° C for 18 hours. 200 ml of water are added to the solution and the mixture is extracted with 100 ml of ethyl acetate. The organic layer was washed twice with water (50 ml) and then washed with 50 ml of a saturated solution of sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.38 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1: 1).

¹ H-NMR (CDCl ₃ )

δ 5.44 (s, 2H), 7.01 (d, J = 6.5 Hz, 1H), 7.30-7.38 (m, 5H), 8.08 (d, J = 6.5 Hz, 1H), 9.18 (s, 1H).

(f) 3-Benzyl-2,4-dichloro-1,3-dihydroimidazo [4,5-c] pyridine

5 ml of phosphorus oxychloride and 0.338 g of phosphorus pentachloride are added to 0.383 g of 3-benzyl-4-chloro-1,3-dihydroimidazo [4,5-c] pyridin-2-one and the mixture is heated under reflux for 24 hours. The solution was concentrated under reduced pressure and the residue was poured into 50 g of ice water. The mixture was extracted with 100 ml of ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.13 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2: 1).

¹ H-NMR (CDCl ₃ )

δ 5.43 (s, 2H), 7.12 (d, J = 6.5 Hz, 1H), 7.30-7.38 (m, 5H), 8.18 (d, J = 6.5 Hz, 1H).

(g) tert-Butyl-4- (3-benzyl-4-chloro-3H-imidazo [4,5-c] pyridin-2-yl) piperazine-1-carboxylate

0.094 g of tert-butyl piperazine-1-carboxylate is added to a solution of 0.127 g of 3-benzyl-2,4-dichloro-1,3-dihydroimidazo [4,5-c] pyridine in 1 ml of N, N-dimethylformamide and the mixture is heated at 150 ° C in two hours. 25 ml of ethyl acetate were added to the mixture and the organic layer was washed three times with water (10 ml) and then 10 ml of an aqueous saturated sodium chloride solution. The organic liquid was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.029 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3: 2).

¹ H-NMR (CDCl ₃ )

δ 1.44 (s, 9H), 3.21-3.25 (m, 4H), 3.49-3.53 (m, 4H), 5.53 (s, 2H), 7.08 (d , J = 6.5 Hz, 1H), 7.30-7.38 (m, 5H), 8.14 (d, J = 6.5 Hz, 1H).

(h) 3-Benzyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

Add 1 ml of water and 1 ml of 35% hydrochloric acid to a solution of 0.029 g of tert-butyl-4- (3-benzyl-4-chloro-3H-imidazo [4,5-c] pyridin-2-yl) piperazine- 1-carboxylate in 2 ml of N, N-dimethylformamide and the mixture was refluxed for 36 hours. The solution was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.006 g of the title compound.

MS m / e (ESI) 310.29 (MH ⁺ -CF ₃ COOH).

Example 338

3- (2-Butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

(a) 2-Bromo-1- (2-butynyl) -1H-imidazole-4,5-dicarbonitrile

69.8 g of potassium carbonate and a solution of 74 ml of 1-bromo-2-butyn in 50 ml of N, N-dimethylformamide are added to a solution of 90.6 g of 2-bromo-1H-imidazole-4,5-dicarbonitrile [CAS No. 50847- 09-1] in 520 ml of N, N-dimethylformamide and the mixture is heated at 50 ° C for 8 hours. 1 L of ethyl acetate and 500 ml of water are added to the solution, and the organic layer is washed twice with water (500 ml), then 500 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, from the fraction eluted with ethyl acetate-hexane (1: 4), 48.0 g of the title compound were obtained.

¹ H-NMR (CDCl ₃ )

δ 1.87 (t, J = 2.3 Hz, 3H); 4.85 (q, J = 2.3 Hz, 2H).

(b) Ethyl 2-bromo-1- (2-butynyl) -5-cyano-1H-imidazole-4-carboxylate

25 ml of concentrated sulfuric acid was added to a solution of 48.0 g of 2-bromo-1- (2-butynyl) -1H-imidazole-4,5-dicarbonitrile in 500 ml of ethanol, and the mixture was refluxed for 110 hours. The reaction solution was cooled to room temperature, then concentrated under reduced pressure. The residue was dissolved in a mixture of 500 ml of ethyl acetate and 500 ml of water, and the pH of the solution was adjusted to 8 using potassium hydroxide. The aqueous layer was extracted with 500 ml of ethyl acetate and the organic layers were combined. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 21.7 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1: 3).

¹ H-NMR (CDCl ₃ )

δ 1.43 (t, J = 7.0 Hz, 3H), 1.87 (t, J = 2.3 Hz, 3H), 4.46 (q, J = 7.0 Hz, 2H), 4 85 (q, J = 2.3 Hz, 2H).

(c) tert-Butyl-4- [1- (2-butynyl) -5-cyano-4-ethoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

25.1 g of the title compound are obtained by using 21.7 g of ethyl 2-bromo-1- (2-butynyl) -5-cyano-1H-imidazole-4-carboxylate according to the method described in Example 115 ( b)

¹ H-NMR (CDCl ₃ )

δ 1.43 (t, J = 7.0 Hz, 3H), 1.49 (s, 9H), 1.87 (t, J = 2.3 Hz, 3H), 3.22-3.26 ( m, 4H), 3.56-3.61 (m, 4H), 4.44 (q, J = 7.0 Hz, 2H), 4.68 (q, J = 2.3 Hz, 2H).

(d) tert-Butyl-4- [1- (2-butynyl) -4-carboxy-5-cyano-1H-imidazol-2-yl] piperazine-1-carboxylate

Add 16 ml of 5 N. an aqueous solution of sodium hydroxide to a solution of 25.1 g of tert-butyl 4- [1- (2-butynyl) -5-cyano-4-ethoxycarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate in 500 ml of ethanol and the mixture was stirred at room temperature for two hours. Then, the solution was concentrated under reduced pressure. The residue is dissolved in a mixture of 1 l of ethyl acetate and 500 ml of water. 50 ml of 2 N are added to the solution. of hydrochloric acid. The organic layer was washed with a saturated solution of sodium chloride (200 ml) and dried over magnesium sulfate. The organic liquid was concentrated under reduced pressure to obtain 23.2 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.87 (t, J = 2.3 Hz, 3H), 3.22-3.26 (m, 4H), 3.56-3.61 (m, 4H ), 4.68 (q, J = 2.3 Hz, 2H).

(e) tert-Butyl-4- [1- (2-butynyl) -5-cyano-4-hydroxymethyl-1H-imidazol-2-yl] piperazine-1-carboxylate

6.9 g of triethylamine are added dropwise and then a solution of 10.19 g of isobutyl chloroformate in 100 ml of tetrahydrofuran to 600 ml of tetrahydrofuran containing 22.9 g of tert-butyl-4- [1- (2-butynyl) -4-carboxy-5 cyano-1H-imidazol-2-yl] piperazine-1-carboxylate, at -10 ° C. After removing the precipitate by filtration, the solution is again cooled to -10ºC. To the solution was added dropwise 100 ml of an aqueous solution of 9.45 g of sodium borohydride. After 1 hour, 500 ml of ethyl acetate and 500 ml of water are added to the solution. The pH of the solution is set to 5 using 1 N. hydrochloric acid, and then adjusted to 10 by adding a saturated solution of sodium bicarbonate. The organic layer was washed successively with water (500 ml) and 500 ml of a saturated solution of sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, from the fraction eluted with ethyl acetate-hexane (4: 1), 19.1 g of the title compound were obtained.

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.84 (t, J = 2.3 Hz, 3H), 2.26 (t, J = 6.3 Hz, 1H), 3.13-3.17 ( m, 4H), 3.53-3.57 (m, 4H), 4.58 (q, J = 2.3 Hz, 2H), 4.64 (d, J = 6.3 Hz, 2H).

(f) tert-Butyl-4- [1- (2-butynyl) -5-cyano-4-formyl-1H-imidazol-2-yl] piperazine-1-carboxylate

3.28 g of manganese dioxide are added to a solution of 1.35 g of tert-butyl-4- [1- (2-butynyl) -5-cyano-4-hydroxymethyl-1H-imidazol-2-yl] piperazine-1-carboxylate in 5 ml of dichloromethane. The reaction solution was stirred at room temperature for 15 hours, then stirred and heated under reflux for five hours. The solution was filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 1.11 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2: 3).

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.88 (t, J = 2.3 Hz, 3H), 3.24-3.28 (m, 4H), 3.59-3.63 (m, 4H ), 4.70 (q, J = 2.3 Hz, 2H), 9.87 (s, 1H).

(g) tert-Butyl-4- [1- (2-butynyl) -5-cyano-4- (2-ethoxycarbonylvinyl) -1H-imidazol-2-yl] piperazine-1-carboxylate

Add 0.038 g of sodium hydride to a solution of 0.243 g of ethyl diethylphosphonoacetate in 5 ml of tetrahydrofuran at 5 ° C and in a nitrogen atmosphere. A solution of 0.310 g of tert-butyl-4- [1- (2-butynyl) -5-cyano-4-formyl-1H-imidazol-2-yl] piperazine-1-carboxylate in 5 ml of tetrahydrofuran is added and the mixture is stirred for 30 minutes. 50 ml of ethyl acetate and 25 ml of 0.1 N are added to the solution. sodium hydroxide solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.380 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3: 7).

¹ H-NMR (CDCl ₃ )

δ 1.33 (t, J = 7.4 Hz, 3H), 1.50 (s, 9H), 1.86 (t, J = 2.3 Hz, 3H), 3.19-3.23 ( m, 4H), 3.55-3.59 (m, 4H), 4.25 (q, J = 7.4 Hz, 2H), 4.59 (q, J = 2.3 Hz, 2H), 6.70 (d, J = 15.8 Hz, 1H); 7.50 (d, J = 15.8 Hz, 1H).

(h) tert-Butyl-4- [1- (2-butynyl) -5-cyano-4- (2-carboxyvinyl) -1H-imidazol-2-yl] piperazine-1-carboxylate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -5-cyano-4- (2-ethoxycarbonylvinyl) -1H-imidazol-2-yl] piperazine-1-carboxylate according to the method described in example 338 (d).

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.86 (t, J = 2.3 Hz, 3H), 3.19-3.23 (m, 4H), 3.55-3.59 (m, 4H ), 4.59 (q, J = 2.3 Hz, 2H), 6.70 (d, J = 15.8 Hz, 1H), 7.50 (d, J = 15.8 Hz, 1H).

(i) tert-Butyl-4- [1- (2-butynyl) -5-cyano-4- (2-azidecarbonylvinyl) -1H-imidazol-2-yl] piperazine-1-carboxylate

Mixture consisting of 0.200 g of tert-butyl-4- [1- (2-butynyl) -5-cyano-4- (2-carboxyvinyl) -1H-imidazol-2-yl] piperazine-1-carboxylate, 0.073 ml of triethylamine and a solution of 0.108 ml of diphenylphosphoryl azide in 2 ml of tert-butyl alcohol, heated at 50 ° C under nitrogen for 4 hours. 50 ml of ethyl acetate are added to the solution and the mixture is washed with 20 ml of water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.178 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2: 3).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.86 (t, J = 2.2 Hz, 3H), 3.19-3.23 (m, 4H), 3.55-3.59 (m, 4H ), 4.59 (q, J = 2.2 Hz, 2H), 6.67 (d, J = 15.4 Hz, 1H), 7.56 (d, J = 15.4 Hz, 1H).

(j) tert-Butyl-4- [4- (2-tert-butoxycarbonylaminovinyl) -1- (2-butynyl) -5-cyano-1H-imidazol-2-yl] piperazine-1-carboxylate

Under nitrogen, a solution of 0.178 g of tert-butyl-4- [1- (2-butynyl) -5-cyano-4- (2-azidecarbonylvinyl) -1H-imidazol-2-yl] piperazine-1-carboxylate is heated under reflux in 10 ml of tert-butyl alcohol for 15 hours. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.169 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (9:11).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.84 (t, J = 2.2 Hz, 3H), 3.16-3.19 (m, 4H), 3.54-3.58 (m, 4H ), 4.51 (q, J = 2.2 Hz, 2H), 5.83 (d, J = 15.0 Hz, 1H), 6.43-6.53 (m, 1H), 7.55 -7.66 (m, 1H).

(k) tert-Butyl-4- [4- (2-tert-butoxycarbonylaminovinyl) -1- (2-butynyl) -5-carbamoyl-1H-imidazol-2-yl] piperazine-1-carboxylate

The title compound was prepared by using tert-butyl-4- [4- (2-tert-butoxycarbonylaminovinyl) -1- (2-butynyl) -5-cyano-1H-imidazol-2-yl] piperazin-1- carboxylate according to the method described in example 332 (b).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.84 (t, J = 2.2 Hz, 3H), 3.21-3.25 (m, 4H), 3.54-3.58 (m, 4H ), 4.68 (q, J = 2.2 Hz, 2H), 5.90 (br.s, 1H), 6.36 (br.s, J = 14.8 Hz, 1H), 6.92 (br.s.d, J = 8.4 Hz, 1H), 7.45 (br.s, 1H), 7.52 (m, 1H).

(l) 3- (2-Butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

Add 0.1 ml of 5 N. hydrochloric acid to a solution of 0.0075 g of tert-butyl-4- [4- (2-tert-butoxycarbonylaminovinyl) -1- (2-butynyl) -5-carbamoyl-1H-imidazol-2-yl] piperazine-1-carboxylate in 0.3 ml of ethanol and the mixture was stirred at room temperature for 15 hours. The solution was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.0043 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.81 (t, J = 2.4 Hz, 3H), 3.45-3.48 (m, 4H), 3.62-3.65 (m, 4H), 5.15 (q, J = 2.4 Hz, 2H), 6.60 (d, J = 7.1 Hz, 1H), 7.18 (d, J = 7.1 Hz, 1H).

MS m / e (ESI) 272.32 (MH ⁺ -CF ₃ COOH).

Example 339

3- (2-Butynyl) -5- (2-phenylethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

(a) tert-Butyl-4- [3- (2-butynyl) -4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridin-2-yl] piperazine-1-carboxylate

The title compound was prepared by using 3- (2-butynyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate according to the method described in Example 258 (a).

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.83 (t, J = 2.3 Hz, 3H), 3.35-3.39 (m, 4H), 3.60-3.64 (m, 4H ), 5.07 (q, J = 2.3 Hz, 2H), 6.55 (d, J = 7.1 Hz, 1H), 6.97 (d, J = 7.1 Hz, 1H).

(b) 3- (2-Butynyl) -5- (2-phenylethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [3- (2-butynyl) -4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridin-2-yl] piperazine-1-carboxylate and (2-bromoethyl) benzene according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 1.83 (t, J = 2.4 Hz, 3H), 3.05 (t, J = 7.3 Hz, 2H), 3.45-3.48 (m, 4H), 3.62- 3.65 (m, 4H), 4.26 (t, J = 7.3 Hz, 2H), 5.18 (q, J = 2.4 Hz, 2H), 6.46 (d, J = 7 , 3 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 7.16-7.30 (m, 5H).

MS m / e (ESI) 376.36 (MH ⁺ -CF ₃ COOH).

Example 340

3- (2-Butynyl) -5- (2-phenoxyethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [3- (2-butynyl) -4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridin-2-yl] piperazine-1-carboxylate and 2-bromoethylphenyl ether according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 1.80 (t, J = 2.4 Hz, 3H), 3.45-3.48 (m, 4H), 3.62-3.65 (m, 4H), 4.30 (t, J = 5.5 Hz, 2H), 4.44 (t, J = 5.5 Hz, 2H), 5.16 (q, J = 2.4 Hz, 2H), 6.59 (d, J = 6 , 1 Hz, 1H), 6.87-6.91 (m, 3H), 7.20-7.24 (m, 2H), 7.50 (d, J = 6.1 Hz, 1H).

MS m / e (ESI) 392.34 (MH ⁺ -CF ₃ COOH).

Example 341

3- (2-Butynyl) -5- (2-oxo-2-phenylethyl) -2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [3- (2-butynyl) -4-oxo-4,5-dihydro-3H-imidazo [4,5-c] pyridin-2-yl] piperazine-1-carboxylate and 2-bromoacetophenone according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 1.79 (t, J = 2.3 Hz, 3H), 3.46-3.50 (m, 4H), 3.64-3.68 (m, 4H), 5.16 (q, J = 2.3 Hz, 2H), 5.61 (s, 2H), 6.65 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.57 (t, J = 8.0 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 2H).

MS m / e (ESI) 392.34 (MH ⁺ -CE ₃ COOH).

Example 342

2- [3- (2-Butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-c] pyridin-5-ylmethyl] benzonitrile trifluoroacetate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridin-2-yl] piperazine-1-carboxylate and 2-bromomethylbenzonitrile according to the method described in example 258 (b).

¹ H-NMR (CD ₃ OD)

δ 1.78 (t, J = 2.3 Hz, 3H), 3.45-3.49 (m, 4H), 3.64-3.67 (m, 4H), 5.14 (q, J = 2.3 Hz, 2H), 5.47 (s, 2H), 6.67 (d, J = 7.0 Hz, 1H), 7.20 (dd, J = 7.2, 1.0 Hz , 1H), 7.46 (td, J = 7.2, 1.0 Hz, 1H), 7.50 (d, J = 7.0 Hz, 1H), 7.60 (td, J = 7, 2, 1.0 Hz, 1H); 7.80 (dd, J = 7.2, 1.0 Hz, 1H).

MS m / e (ESI) 387.34 (MH ⁺ -CE ₃ COOH).

Example 343

Methyl 3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -4,5-dihydroimidazo [4,5-c] pyridine-6-carboxylate trifluoroacetate

(a) tert-Butyl-4- [1- (2-butynyl) -4-hydroxymethyl-5-thiocarbamoyl-1H-imidazol-2-yl] piperazine-1-carboxylate

Add 10 ml of a 50% aqueous solution of ammonium sulfide to a solution of 3.596 g of tert-butyl-4- [1- (2-butynyl) -5-cyano-4-hydroxymethyl-1H-imidazol-2-yl] piperazin-1- carboxylate in 50 ml of ethanol and the mixture was stirred at room temperature for 16 hours. 400 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 3.221 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (4: 1).

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.84 (t, J = 2.4 Hz, 3H), 3.17-3.21 (m, 4H), 3.54-3.60 (m, 4H ), 3.62 (t, J = 5.8 Hz, 1H), 4.68 (d, J = 5.8 Hz, 2H), 5.05 (q, J = 2.4 Hz, 2H), 7.35 (br s, 1H); 8.46 (br s, 1H).

(b) tert-Butyl-4- [4- (tert-butyldiphenylsilanyloxymethyl) -1- (2-butynyl) -5-thiocarbamoyl-1H-imidazol-2-yl] piperazine-1-carboxylate

0.668 g of imidazole and 2.70 g of tert-butylchlorodiphenylsilane are added to a solution of 3.221 g of tert-butyl-4- [1- (2-butynyl) -4-hydroxymethyl-5-thiocarbamoyl-1H-imidazol-2-yl] piperazin-1 β-carboxylate in 25 ml of N, N-dimethylformamide and the mixture was stirred at room temperature for 16 hours. 300 ml of ethyl acetate are added to the solution and the organic layer is washed three times with 100 ml of water and then 100 ml of a saturated solution of sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 4.357 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2: 3).

¹ H-NMR (CDCl ₃ )

δ 1.05 (s, 9H), 1.49 (s, 9H), 1.84 (t, J = 2.4 Hz, 3H), 3.06-3.11 (m, 4H), 3, 53-3.57 (m, 4H), 4.74 (s, 2H), 5.19 (q, J = 2.4 Hz, 2H), 7.31 (br.s, J = 4.1 Hz , 1H), 7.37 (t, J = 7.2 Hz, 4H), 7.44 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 7.2 Hz, 4H ), 9.28 (brd, J = 4.1 Hz, 1H).

(c) tert-Butyl-4- [4- (tert-butyldiphenylsilanyloxymethyl) -1- (2-butynyl) -5-methylsulfanylcarbonimidoyl-1H-imidazol-2-yl] piperazine-1-carboxylate

1.23 g of trimethyloxonium tetrafluoroborate are added to a solution of 4.351 g of tert-butyl-4- [4- (tert-butyldiphenylsilanyloxymethyl) -1- (2-butynyl) -5-thiocarbamoyl-1H-imidazol-2-yl] piperazin-1- carboxylate in 100 ml of dichloromethane and the mixture was stirred at room temperature for 15 hours. 300 ml of ethyl acetate are added to the solution and the organic layer is washed successively with 100 ml of a saturated solution of sodium bicarbonate and 100 ml of a saturated solution of ammonium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 4.439 g of the title compound.

¹ H-NMR (CDCl ₃ )

δ 1.05 (s, 9H), 1.49 (s, 9H), 1.84 (br s, 3H), 2.36 (br s, 3H), 3.11-3.15 (m , 4H), 3.54-3.58 (m, 4H), 4.63 (br s, 2H), 4.66 (br s, 2H), 7.37 (t, J = 7.2 Hz, 4H), 7.44 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 7.2 Hz, 4H).

(d) tert-Butyl-4- [1- (2-butynyl) -4-hydroxymethyl-5-methylsulfanylcarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

Add 30 ml of 5 N. hydrochloric acid to a solution of 5.05 g of tert-butyl-4- [4- (tert-butyl diphenylsilanyloxymethyl) -1- (2-butynyl) -5-methylsulfanylcarbonimidoyl-1H-imidazol-2-yl] piperazine-1-carboxylate in 100 ml of tetrahydrofuran and the mixture was stirred at room temperature for 22 hours. The solution was concentrated under reduced pressure. The residue was dissolved in 100 ml of dichloromethane and 2.05 g of di-tert-butyl dicarbonate was added to this solution. The solution is alkalinized 5 N. sodium hydroxide solution and the mixture is stirred for 2 hours. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.24 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2: 3).

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.84 (t, J = 2.3 Hz, 3H), 2.47 (s, 3H), 3.21-3.25 (m, 4H), 3, 27 (t, J = 5.6 Hz, 1H), 3.56-3.60 (m, 4H), 4.81 (q, J = 2.4 Hz, 2H), 4.89 (d, J = 5.6 Hz, 2H).

(e) tert-Butyl-4- [1- (2-butynyl) -4-formyl-5-methylsulfanylcarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate

The title compound was prepared by using tert-butyl-4- [1- (2-butynyl) -4-hydroxymethyl-5-methylsulfanylcarbonyl-1H-imidazol-2-yl] piperazine-1-carboxylate according to the method described in Example 115 (g).

¹ H-NMR (CDCl ₃ )

δ 1.48 (s, 9H), 1.84 (t, J = 2.3 Hz, 3H), 2.58 (s, 3H), 3.22-3.26 (m, 4H), 3, 56-3.60 (m, 4H), 4.80 (q, J = 2.4 Hz, 2H), 9.88 (s, 1H).

(f) 2- (4-tert-butoxycarbonylpiperazin-1-yl) -3- (2-butynyl) -4-oxo-3,4-dihydroimidazo [4,5-c] pyridine 5-benzyl, 6-methyl ester -5,6-dicarboxylic acid

Add 0.079 g of 1,8-diazabicyclo [5.4.0] -7-undecene and then 5 ml of dichloromethane containing 0.194 g of tert-butyl-4- [1- (2-butynyl) -4-formyl-5-methylsulfanylcarbonyl -1H-imidazol-2-yl] piperazine-1-carboxylate, to a solution of 0.174 g of methylbenzyloxycarbonylamino (dimethoxyphosphoryl) acetate in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.147 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3: 2).

¹ H-NMR (CDCl ₃ )

δ 1.49 (s, 9H), 1.83 (t, J = 2.3 Hz, 3H), 3.37-3.41 (m, 4H), 3.59-3.64 (m, 4H ), 3.83 (s, 3H), 5.04 (q, J = 2.3 Hz, 2H), 5.46 (s, 2H), 7.33-7.38 (m, 3H), 7 41 (s, 1H); 7.45-7.48 (m, 2H).

(g) tert-Butyl-4- [3- (2-butynyl) -4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo [4,5-c] pyridin-2-yl] piperazine- 1-carboxylate

Add 0.023 g of sodium to 2 ml of methanol in a nitrogen atmosphere. After the evolution of hydrogen ceased, 0.147 g of 2- (4-tert-butoxycarbonylpiperazin-1-yl) -3- (2-butynyl) -4-oxo-3,4-dihydroimidazo [5-benzyl, 6-methyl ether] was added to this solution. 4,5-c] pyridine-5,6-dicarboxylic acid in 2 ml of methanol. The mixture was stirred at room temperature for 16 hours. Then add to this solution 40 ml of ethyl acetate, 20 ml of a 5% aqueous solution of ammonium chloride and 1 ml of 1 N. of hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.108 g of the title compound was obtained from the fraction eluted with ethyl acetate.

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.83 (t, J = 2.3 Hz, 3H), 3.20 (s, 9H), 3.37-3.41 (m, 4H), 3, 59-3.64 (m, 4H), 5.07 (q, J = 2.3 Hz, 2H), 6.82 (s, 1H), 8.60 (br s, 1H).

(h) Methyl 3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -4,5-dihydroimidazo [4,5-c] pyridine-6-carboxylate trifluoroacetate

The title compound was prepared by using tert-butyl-4- [3- (2-butynyl) -4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo [4,5-c] pyridine- 2-yl] piperazin-1-carboxylate according to the method described in example 338 (l).

¹ H-NMR (CD ₃ OD)

δ 1.81 (t, J = 2.3 Hz, 3H), 3.45-3.49 (m, 4H), 3.64-3.67 (m, 4H), 3.95 (s, 3H ), 5.17 (q, J = 2.3 Hz, 2H), 7.35 (s, 1H).

MS m / e (ESI) 330.16 (MH ⁺ -CF ₃ COOH).

Example 344

Methyl 3- (2-butynyl) -5-methyl-4-oxo-2- (piperazin-1-yl) -4,5-dihydroimidazo [4,5-c] pyridine-6-carboxylate trifluoroacetate

Add 0.024 g of potassium carbonate and 0.027 ml of methyl iodide to a solution of 0.030 g of tert-butyl-4- [3- (2-butynyl) -4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo [4,5- c] pyridin-2-yl] piperazine-1-carboxylate in 2 ml of N, N-dimethylformamide and the mixture was heated at 50 ° C for 48 hours. 2 ml of ethyl acetate and 2 ml of water are added to this solution. The aqueous layer was extracted with 1 ml of ethyl acetate. The organic layers are combined and then divided into two equal parts. One part is concentrated by purging with nitrogen gas and the residue is dissolved in 0.5 ml of methanol. The solution is combined with 0.1 ml of 5 N. hydrochloric acid and the mixture was incubated for 1 hour. The solvent was removed and the residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.007 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.81 (t, J = 2.4 Hz, 3H), 3.45-3.48 (m, 4H), 3.62-3.65 (m, 4H), 3.74 (s, 3H ), 3.94 (s, 3H), 5.17 (q, J = 2.4 Hz, 2H), 7.25 (s, 1H).

MS m / e (ESI) 344.30 (MH ⁺ -CF ₃ COOH).

Example 345

3- (2-Butynyl) -5-methyl-4-oxo-2- (piperazin-1-yl) -4,5-dihydroimidazo [4,5-c] pyridin-6-carboxylamide trifluoroacetate

Another part of the solution obtained in Example 344 was concentrated by purging with nitrogen gas. The residue is treated with ammonia water (1 ml, 28% ammonia). The solution was heated to boiling under reflux in a sealed tube for 48 hours. The solution was concentrated under reduced pressure. The subsequent synthesis steps were carried out in accordance with the method that was used in example 115 (i). Thus, 0.010 g of the title compound is synthesized.

MS m / e (ESI) 329.32 (MH ⁺ -CF ₃ COOH).

Example 346

Methyl-3- (2-butynyl) -4-oxo-5- (2-oxo-2-phenylethyl) -2- (piperazin-1-yl) -4,5-dihydroimidazo [4,5-c] pyridine trifluoroacetate -6-carboxylate

The title compound was prepared by using tert-butyl-4- [3- (2-butynyl) -4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo [4,5-c] pyridine- 2-yl] piperazin-1-carboxylate and 2-bromoacetophenone according to the method described in example 344.

MS m / e (ESI) 448.31 (MH ⁺ -CF ₃ COOH).

Example 347

Methyl 3- (2-butynyl) -5- (2-cyanobenzyl) -4-oxo-2- (piperazin-1-yl) -4,5-dihydroimidazo [4,5-c] pyridine-6-carboxylate trifluoroacetate

The title compound was prepared by using tert-butyl-4- [3- (2-butynyl) -4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo [4,5-c] pyridine- 2-yl] piperazin-1-carboxylate and 2-bromomethylbenzonitrile according to the method described in example 344.

MS m / e (ESI) 445.32 (MH ⁺ -CF ₃ COOH).

Example 348

3- (2-Butynyl) -5- (2-cyanobenzyl) -4-oxo-2- (piperazin-1-yl) -4,5-dihydroimidazo [4,5-c] pyridin-6-carboxylamide trifluoroacetate

The title compound was prepared by using tert-butyl-4- [3- (2-butynyl) -4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo [4,5-c] pyridine- 2-yl] piperazin-1-carboxylate and 2-bromomethylbenzonitrile according to the method described in example 345.

MS m / e (ESI) 430.34 (MH ⁺ -CF ₃ COOH).

Example 349

1- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -1,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) -1 3- (2-Butynyl) -2-chloro-5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one

and

(a) -2 1- (2-Butynyl) -2-chloro-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one

Add 0.166 g of potassium carbonate and 0.106 μl of 2-butynyl bromide to a solution of 0.184 g of 2-chloro-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one in 10 ml of N, N-dimethylformamide and the mixture stirred at room temperature for 18 hours. 50 ml of ethyl acetate are added to this solution and the mixture is washed three times with water (20 ml) and then with a saturated solution of sodium chloride (20 ml). The organic liquid was dried over magnesium sulfate and concentrated under reduced pressure. The residue is then purified by silica gel column chromatography. Thus, 0.175 g of 3- (2-butynyl) -2-chloro-5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one is obtained from the fraction eluted with hexane-ethyl acetate (4: 1 ), and 0.033 g of 1- (2-butynyl) -2-chloro-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one from the fraction eluted with hexane-ethyl acetate (2: 3 )

3- (2-Butynyl) -2-chloro-5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one :

¹ H-NMR (CDCl ₃ )

δ 1.82 (t, J = 2.3 Hz, 3H), 3.87 (s, 3H), 5.32 (q, J = 2.3 Hz, 2H), 8.19 (s, 1H) .

1- (2-Butynyl) -2-chloro-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one :

¹ H-NMR (CDCl ₃ )

δ 1.87 (t, J = 2.3 Hz, 3H), 3.91, (s, 3H), 4.90 (q, J = 2.3 Hz, 2H), 8.20 (s, 1H )

(b) tert-Butyl-4- [1- (2-butynyl) -5-methyl-4-oxo-4,5-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] piperazin- 1-carboxylate

The title compound was prepared by using 1- (2-butynyl) -2-chloro-5-methyl-1,5-dihydroimidazo [4,5-d] pyridazin-4-one and tert-butylpiperazine-1-carboxylate by the method described in example 119 (c).

¹ H-NMR (CDCl ₃ )

δ 1.50 (s, 9H), 1.87 (t, J = 2.3 Hz, 3H), 3.30-3.34 (m, 4H), 3.59-3.63 (m, 4H ), 3.90 (s, 3H), 4.70 (q, J = 2.3 Hz, 2H), 8.11 (s, 1H).

(c) 1- (2-Butynyl) -5-methyl-2- (piperazin-1-yl) -1,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

The title compound was prepared by using tert-butyl-4- [5-methyl-1- (2-butynyl) -4-oxo-4,5-dihydro-1H-imidazo [4,5-d] pyridazin- 2-yl] piperazin-1-carboxylate according to the method described in example 115 (i).

¹ H-NMR (CD ₃ OD)

δ 1.84 (t, J = 2.4 Hz, 3H), 3.44-3.48 (m, 4H), 3.58-3.62 (m, 4H), 3.86 (s, 3H ), 4.96 (q, J = 2.4 Hz, 2H), 8.39 (s, 1H).

MS m / e (ESI) 287.17 (MH ⁺ -CF ₃ COOH).

Example 350

Trifluoroacetate 2 - [(1R *, 2R *) 2-aminocyclohexylamino] -3- (2-butynyl) -5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one

The title compound was prepared by reacting 3- (2-butynyl) -2-chloro-5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one and trans-1,2-cyclohexanediamine by the method that was used in example 119 (c), with purification of the product by reverse phase high performance liquid chromatography.

¹ H-NMR (CD ₃ OD)

δ 1.39-1.49 (m, 2H), 1.50-1.61 (m, 2H), 1.80 (t, J = 2.3 Hz, 3H), 1.85-1.92 (m, 2H), 2.11-2.18 (m, 2H), 3.19 (td, J = 11.0, 4.1 Hz, 1H), 3.80 (s, 3H), 3, 93 (td, J = 11.0, 4.2 Hz, 1H), 4.91 (d q, J = 18.0, 2.3 Hz, 1H), 5.44 (d q, J = 18, 0, 2.3 Hz, 1H), 8.07 (s, 1H).

Mc m / e (ESI) 315.19 (MH ⁺ -CF ₃ COOH).

Example 351

Trifluoroacetate 2 - [(1R *, 2S *) 2-aminocyclohexylamino] -3- (2-butynyl) -5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one

The title compound was prepared by reacting 3- (2-butynyl) -2-chloro-5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one and cis-1,2-cyclohexanediamine by the method that was used in example 119 (c), with purification of the product by reverse phase high performance liquid chromatography.

¹ H-NMR (CD ₃ OD)

δ 1.54-1.68 (m, 3H), 1.71-1.81 (m, 2H), 1.83 (t, J = 2.4 Hz, 3H), 1.85-1.91 (m, 2H), 1.91-2.01 (m, 1H), 3.69 (m, 1H), 3.80 (s, 3H), 4.37 (m, 1H), 5.04 ( q q, J = 18.3, 2.4 Hz, 1H), 5.55 (q q, J = 18.3, 2.4 Hz, 1H), 8.09 (s, 1H).

MS m / e (ESI) 315.27 (MH ⁺ -CF ₃ COOH).

Example 352

3- (2-Butynyl) -5-methyl-2- (1,2,3,6-tetrahydropyridin-4-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one trifluoroacetate

(a) 5-Methyl-2- (pyridin-4-yl) -1,5-dihydroimidazo [4,5-d] pyridazin-4-one

0.560 g of 4,5-diamino-2-methyl-2H-pyridazin-3-one and 0.535 g of 4-pyridinecarbaldehyde are added to 10 ml of nitrobenzene and the mixture is heated at 190 ° C under nitrogen for three hours. The reaction solution was cooled and the precipitate was collected by filtration to obtain 0.381 g of the title compound.

¹ H-NMR (DMSO-d ₆ )

δ 3.78 (s, 3H), 8.14 (d, J = 6.0 Hz, 2H), 8.48 (s, 1H), 8.76 (d, J = 6.0 Hz, 2H) .

MS m / e (ESI) 228.1 (MH ⁺ ).

(b) 3- (2-Butynyl) -5-methyl-2- (pyridin-4-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one

The title compound was prepared by using 5-methyl-2- (pyridin-4-yl) -1,5-dihydroimidazo [4,5-d] pyridazin-4-one and 2-butynyl bromide according to the method described in Example 119 (d).

¹ H-NMR (CDCl ₃ )

δ 1.84 (t, J = 2.3 Hz, 3H), 3.91 (s, 3H), 5.37 (q, J = 2.3 Hz, 2H), 7.89 (d, J = 6.1 Hz, 2H), 8.32 (s, 1H), 8.85 (d, J = 2.3 Hz, 2H).

(c) 4- [1- (2-Butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl] -1- (4) chloride -methoxybenzyl) pyridinium

0.045 g of 3- (2-butynyl) -5-methyl-2- (pyridin-4-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one and 0.060 μl of para-methoxybenzyl chloride are added to 0.100 ml of N, N-dimethylformamide and the mixture was stirred at 65 ° C under nitrogen for 4 hours. The reaction solution was cooled and 1 ml of acetone and 1 ml of diethyl ether were added thereto. The precipitate was collected by filtration to obtain 0.060 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.75 (t, J = 2.3 Hz, 3H), 3.74 (s, 3H), 3.77 (s, 3H), 5.64 (q, J = 2.3 Hz, 2H) 5.86 (s, 2H), 7.05 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 8.43 (s, 1H) 8.70 (d, J = 6.3 Hz, 2H); 9.24 (d, J = 6.3 Hz, 2H).

(d) 3- (2-Butynyl) -2- [1- (4-methoxybenzyl) -1,2,3,6-tetrahydropyridin-4-yl] -5-methyl-3,5-dihydroimidazo [4,5 -d] pyridazin-4-one

0.020 g of sodium borohydride is added to a solution of 0.060 g of 4- [1- (2-butynyl) -6-methyl-7-oxo-6,7-dihydro-1H-imidazo [4,5-d] pyridazin-2-yl chloride ] -1- (4-methoxybenzyl) pyridinium in 5 ml of methanol and the mixture was stirred for 1 hour. Add to the solution 15 ml of water and 0.1 ml of 5 N. hydrochloric acid in order to decompose a reducing agent. Then the solution is alkalinized by adding 1 ml of 5 N. sodium hydroxide solution and the mixture is extracted with 30 ml of ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.033 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:19).

¹ H-NMR (CDCl ₃ )

δ 1.80 (t, J = 2.4 Hz, 3H), 2.71-2.78 (m, 4H), 3.25-3.28 (m, 2H), 3.62 (s, 2H ), 3.82 (s, 3H), 3.87 (s, 3H), 5.30 (q, J = 2.4 Hz, 2H), 6.61 (m, 1H), 6.89 (d , J = 9.1 Hz, 2H), 7.30 (d, J = 9.1 Hz, 2H), 8.22 (s, 1H).

(e) 3- (2-Butynyl) -5-methyl-2- (1,2,3,6-tetrahydropyridin-4-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4- trifluoroacetate she

Add 0.10 ml of 1-chloroethylchloroformate to a solution of 0.033 g of 3- (2-butynyl) -2- [1- (4-methoxybenzyl) -1,2,3,6-tetrahydropyridin-4-yl] -5-methyl- 3,5-dihydroimidazo [4,5-d] pyridazin-4-one in 2 ml of 1,2-dichloroethane and the mixture was heated under reflux for 90 minutes. 5 ml of methanol was added to the solution, and the mixture was further heated under reflux for 4 hours. Then, the solution was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography to give 0.010 g of the title compound.

¹ H-NMR (CD ₃ OD)

δ 1.81 (t, J = 2.4 Hz, 3H), 2.89-2.94 (m, 2H), 3.52 (t, J = 6.2 Hz, 2H), 3.84 ( s, 3H), 4.01 (q, J = 2.8 Hz, 2H), 5.27 (q, J = 2.4 Hz, 2H), 6.67 (m, 1H), 8.30 ( s, 1H).

MS m / e (ESI) 284.22 (MH ⁺ -CF ₃ COOH).

[Test Example 1] DPPIV Inhibitory Activity Assay

Dissolved in reaction buffer (50 mM Tris-HCl (pH 7.4) / 0.1% BSA (bovine serum albumin)) DPP-IV produced from pork kidneys at a concentration of 10 μmol / ml. This solution (110 μl) was combined with 15 μl of reagent, and then the mixture was kept at room temperature for 20 minutes. To this solution, 25 μl of a solution (2 mmol / L) of Gly-Pro-para-nitroanilide (to a final concentration of 0.33 mmol / L) was added in order to initiate an enzymatic reaction. The reaction time is 20 minutes. In order to interrupt the reaction, 25 μl of 1 N was added to the reaction mixture. phosphoric acid solution. The absorption of this solution is recorded at a wavelength of 405 nm and then the degree of inhibition of the enzymatic reaction is calculated in order to determine the concentration of inhibition by 50%, IC ₅₀ .

Table 1 Example Number IC ₅₀ (μmol / L) Example 1 0.287 Example 4 0.211 Example 7 0.401 Example 9 0.141 Example 12 0.183 Example 13 0.125 Example 16 0.272 Example 20 0.152 Example 22 0.170 Example 29 0.310 Example 53 0.0469 Example 64 0,126 Example 73 0,0334 Example 76 0.0865 Example 79 0,0357 Example 82 0.161 Example 83 0,0274 Example 86 0,00408 Example 88 0,00289 Example 98 0.00969 Example 109 1.48 Example 119 0.154 Example 120 0.116 Example 122 0.0153 Example 129 0.115 Example 142 0,0685 Example 146 0.0817 Example 159 0,0377 Example 229 0,00897 Example 230 0,000890 Example 234 0,00174 Example 235 0,00144 Example 238 0.00119 Example 243 0.00215 Example 248 0,00640 Example 266 0.00155 Example 267 0,00722 Example 297 0.00622 Example 311 0,0775 Example 341 0,00732

[Test Example 2]

The effect of compounds on glucose tolerance in normal mice (in vivo test)

Animals: Male C57BL / 6N mice (purchased from Charles River Japan, Inc.).

Method: preparation and administration of test compounds

Each test compound is suspended in a 0.5% methyl cellulose (MC) solution at the concentration indicated in the table below. A suspension of the test compound and NVP DPP728 (US Patent No. 6011155) or a 0.5% solution of MC, which is used as the medium for the control group, is administered orally at a dose of 10 ml / kg. After 30 minutes, an oral glucose solution was given at a dosage of 10 ml / kg. The oral glucose dosage is 2 g / kg.

[Blood collection and determination of blood glucose]

Immediately prior to administration of the test compound and NVP DPP728, immediately prior to administration of the glucose solution, and 30, 60 and 120 minutes after administration, the tail vein is slightly incised with a razor blade without anesthesia to allow blood to flow out. 10 μl of blood is collected and immediately combined with 140 μl of a 0.6 M perchloric acid solution. The sample is subjected to centrifugation with an acceleration of 1500 g at a temperature of 4ºC for 10 minutes in a centrifuge with freezing GS-6KR (Beckman Corp.). The glucose concentration in the resulting liquid above the precipitate was determined using the Glucose CII TEST WAKO kit (Wako Pure Chemical Industries).

results

The area under the curve "change in glucose over time" (AUC _0-120 ; area under the curve) was obtained from the time dependence of glucose from the start of glucose up to 120 minutes after administration; determination is carried out for each group treated with 0.5% MC solution, the group treated with NVP DPP728 and the group treated with the test compound. The glucose tolerance improvement coefficient for the test compound is determined by taking AUC _0-120 for the group treated with 0.5% MC solution as 100%, and AUC _0-120 for the group treated with DPP728 NVP (dose 10 mg / kg) , for 0%, in accordance with the following formula.

Glucose tolerance improvement coefficient (%) = (AUC _0-120 for the group treated with the test compound - AUC _0-120 for the group treated with NVP DPP728 (10 mg / kg)) / AUC _0-120 for the group treated with 0.5 % solution of MC, - AUC _0-120 for the group treated with NVP DPP728 (10 mg / kg)) × 100.

The lower this coefficient (in%), the greater the improvement in glucose tolerance.

It has been found that some of the new condensed imidazole derivatives of the present invention have a significant effect on glucose tolerance in normal mice during the in vivo experiment described above, which involves oral administration of the compounds at a dosage of 0.1-10 (mg / kg).

[Test Example 3]

Acceptable Timeline for In vivo Testing

Ideally, a drug for treating afternoon hyperglycemia is required to have comparable efficacy in treating afternoon hyperglycemia, both when administered immediately before meals and when administered 1 hour before meals. Thus, an excellent drug exhibiting increased efficacy can be developed by expanding an acceptable timeline for drug administration.

Method

The corresponding tests described below were carried out in conjunction with the in vivo test (administration of the drug in 0.5 hour) as described in Test Example 2.

1. The test compound is administered simultaneously with 2 g / kg glucose (the test compound is suspended in an aqueous solution of 0.5% methylcellulose; the solution is combined with an equal volume of glucose solution; the mixture is administered orally at a dose of 10 ml / kg).

2. The test compound is administered 1 hour before glucose supply (2 g / kg) (test compound is suspended in an aqueous solution of 0.5% methylcellulose and administered orally one hour before oral administration of the glucose solution; each compound is given orally at a dosage of 10 ml / kg).

The glucose tolerance improvement coefficient is evaluated in each trial. An acceptable timeline for drug administration can be determined by evaluating: whether a comparable degree of improvement is achieved with two types of administration, preferably when the doses differ 3 times or less, and most preferably by evaluating: whether a comparable degree of improvement is achieved with two types of administration, when doses are the same. It turned out that such representative compounds of the present invention (including compounds selected from the group consisting of those shown in examples 82, 119, 120, 122, 229 and 267) have sufficiently wide intervals of an acceptable timing of administration, such as indicated above.

[Test Example 4]

Purpose: the effect of the test compound on blood glucose in starving male Wistar rats (in vivo test)

Animals: Male Wistar rats (available from Charles River Japan, Inc.).

Method: preparation and administration of test compounds

The test compound is suspended in a 0.5% methylcellulose (MC) solution and orally administered at a dose of 5 ml / kg. The control group of animals is treated with a 0.5% solution of MC. The solution is administered orally at a dosage of 5 ml / kg.

[Blood collection and determination of blood glucose]

Immediately prior to administration of the test compound or 0.5% MC solution and 0.5, 1 and 3 hours after administration without anesthesia, the tail vein is slightly incised with a razor blade so that blood flows out. 10 μl of blood are collected and combined with 140 μl of a 0.6 M perchloric acid solution. The sample is centrifuged at an acceleration of 3000 g at 4 ° C for 10 minutes and the glucose concentration in the resulting liquid above the precipitate is determined using the CII TEST WAKO kit (Wako Pure Chemical Industries).

results

It was found that some of the new condensed imidazole derivatives of the present invention (in particular, compounds selected from the group consisting of those shown in examples 82, 119, 120, 122, 229 and 267) do not significantly affect the glucose content in the samples blood taken at any time compared to a control group treated with one medium in an in vivo experiment, as described above, where each compound is orally administered at a dosage of 10-30 mg / kg.

[Test Example 5]

The effect of the test compound on the glucose tolerance of male Zucker fa / fa rats (model animals with obese diabetes mellitus type II) (in vivo test)

Animals: Zucker fa / fa male rats (available from Charles River Japan, Inc.).

Method: preparation and administration of test compounds

The test compound is suspended in a 0.5% methyl cellulose (MC) solution. A suspension of the test compound or 0.5% MC solution, which is used in the control group treated with the medium, is given orally at a dosage of 5 ml / kg. After 0.5 hours, a glucose solution at a dosage of 5 ml / kg was orally given. The dose of glucose administered orally is 2 g / kg.

Method: blood sampling and determination of glucose, insulin and GLP-1

Immediately prior to administration of the test compound or 0.5% MC solution, immediately before glucose administration, and 0.5, 1, 2, and 3 hours after glucose administration, without anesthesia, the tail vein is slightly cut with a razor blade to allow blood to flow out. 250 μl of blood is collected using a heparin-coated capillary and transferred to a centrifuge tube. The sample is centrifuged with an acceleration of 10,000 g at 4ºC for 2 minutes. The content of insulin and GLP-1 is determined in the formed liquid above the precipitate using an insulin analysis kit (Morinaga Biochemical Institute) and Active GLP-1 ELISA kit (Linco), respectively. At the same time, 10 μl of blood was collected and combined with 140 μl of a 0.6 M perchloric acid solution. The sample is centrifuged at an acceleration of 3000 g at 4 ° C for 10 minutes and the glucose concentration in the resulting liquid above the precipitate is determined using the CII TEST WAKO kit (Wako Pure Chemical Industries). Only the glucose content is determined three hours after glucose administration.

results

The area under the curve "change in glucose over time" (AUC _{Glu (0-3 h)} ) from the start of glucose up to 3 hours after administration; the area under the curve of insulin content over time (AUC _{ins (0-2 h)} ) and the area under the curve of GLP-1 over time (AUC _{GLP-1 (0-2 h)} ) is determined for each group of animals treated with 0.5% a solution of MC, and for each group treated with the test compound. The change in glucose tolerance, the change in insulin content and the change in GLP-1 caused by the test compound is determined by taking the AUC value for the group treated with 0.5% MC solution as 100%, in accordance with the following formulas:

* The degree of change in glucose tolerance (%) = (AUC _0-3h for the group treated with the test compound / AUC _0-2h for the group treated with a 0.5% MC solution) × 100;

* The degree of change in insulin content and GLP-1 (%) = AUC _{0-2 h} for the group treated with the test compound / AUC _{0-2 h} for the group treated with a 0.5% MC solution) × 100.

It was found that some of the new condensed imidazole derivatives of the present invention (in particular, compounds selected from the group consisting of those shown in examples 82, 119, 120, 122, 229 and 267) change the content of insulin and GLP-1 to a degree more than 100% and show a degree of change in glucose tolerance of less than 100% in an in vivo experiment, as described above, where each compound is orally administered at a dosage of 0.10-10 (mg / kg).

[Test Example 6]

Assessment for an enzyme (cytochrome P450) metabolizing a drug

The inhibitory activity of IC ₅₀ is determined using the expression system for recombinant P450 and fluorescent substrates (GENTEST Corp.), which are shown in tables 2 and 3, according to the test procedure Procedure (WWW.gentest.com) and obtained from GENTEST Corp. The estimated molecular species P450 are five molecular species, CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. The applicable experimental conditions are shown below. Fluorescence intensity is determined using a plate counter (CYTO FLUOR Multi-Well Plate Reader Series 4000; PerSeptive Biosystems Corp.). The degree of inhibition is defined as the average of nine independent measurements per second, using fluorescence emitted by the metabolite of the fluorescent substrate as an indicator of intensity.

Table 2 shows the substrates, metabolites, inhibitors, excitation wavelengths, and fluorescence wavelengths used in this analysis.

table 2 Molecular Varieties of p450 Substrate Metabolite Inhibitor Excitation wavelength (nm) Fluorescence wavelength
(nm) CYP1A2 Cec Chc α-naphthoflavone 409 460 CYP2C9 Mfc Hfc sulfaphenazole 409 530 CYP2C19 Cec Chc tranylcypropine 409 460 CYP2D6 AMMC Ahmc quinidine 390 460 CYP3A4 Bfc Hfc ketoconazole 409 530

Abbreviations for substrates and metabolites are shown in table 3.

Table 3 Cec 3-cyano-7-ethoxycoumarin SNA 3-cyano-7-hydroxycoumarin Mfc 7-methoxy-4- (trifluoromethyl) coumarin Hfc 7-hydroxy-4- (trifluoromethyl) coumarin Cec 7-ethoxy-3-cyanocoumarin SNA 7-hydroxy-3-cyanocoumarin AMMC 3- [2- (N, N-diethyl-N-methylamino) ethyl] -7-methoxy-4-methylcoumarin ANMS 3- [2- (N, N-diethylamino) ethyl] -7-hydroxy-4-methylcoumarin Bfc 7-benzyloxy-4- (trifluoromethyl) coumarin Hfc 7-hydroxy-4- (trifluoromethyl) coumarin

Analysis results

The compounds of the present invention are evaluated for their ability to inhibit metabolic reactions due to P450 in test example 6. This experiment demonstrated that representative compounds of the present invention (including compounds selected from the group consisting of those specified in examples 82, 119, 120, 122, 229, and 267) have IC ₅₀ values of 10 μM or higher with respect to five molecules from the P450 group, namely the molecular species, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

[Test Example 7]

HERG channel current suppression

(1) The hERG channel current inhibition activity is evaluated according to a report by Zhou Z. et al. In Biophysical Journal, 74 (1), 230-241 (1998).

(2) This experiment was carried out using HEK-293 cells into which the hERG channel gene (subtype 1) was introduced (cell line established by the authors of this invention).

(3) One or several days before the experiment, the cells are seeded on a glass cup coated with polylysine. Cells are cultured until the day of the experiment. At the beginning of the experiment, a glass cup with seeded cells is transferred to a bath for measurement. The channel current hERG is measured using the voltage terminals using the plug connector technique. Current is measured using a current amplifier (Axon Instruments). Current is recorded and analyzed using pCLAMP software (Axon Instruments).

(4) The hERG channel current is induced in cells by applying a depolarizing pulse with a fixing potential from -80 to +20 mV for 5 seconds and to -50 mV for 4 seconds, at intervals of 20 seconds. After stabilization of the current in the control solution, the cells are perfused with solutions containing various concentrations of the test compounds.

(5) The current amplitude of the hERG channel is defined as the peak value of the loop current, which is observed when the voltage is restored to -50 mV. The inhibitory ability of the test compound for the channel current hERG (IC ₅₀ ) is evaluated by changing the peak value of the loop current after adding the test compound at different concentrations. The peak value of the loop current recorded for a normal solution is assumed to be 100%.

Test results

Representative compounds of the present invention (including compounds selected from the group consisting of the compounds shown in examples 82, 119, 120, 122, 229 and 267) are evaluated by the ability of the test compounds to inhibit the hERG channel current in test example 7. IC values ₅₀ for these compounds was 30 μM or higher.

Structural formulas for the compounds in the above production examples and in the examples are shown below.

Industrial applicability

The present invention provides fused imidazole derivatives having DPPIV inhibitory activity.

Therefore, the condensed imidazole derivatives of the present invention can be used as therapeutic and prophylactic drugs, for example, in the treatment of diabetes mellitus, obesity, hyperlipidemia, AIDS, osteoporosis, gastrointestinal disorders, angiogenesis, infertility, as anti-inflammatory and anti-allergic drugs, immunomodulating agents, hormonal regulators, anti-rheumatic drugs and antitumor drugs.

In addition, using an index of the ability of these compounds to improve glucose tolerance, the compounds were tested in order to evaluate their effectiveness after oral administration. Thus, the sufficient efficacy of these compounds was confirmed and their applicability as pharmaceuticals was demonstrated.

Claims (33)

1. The compound represented by the following formula, or its salt or hydrate

where T ¹ represents a monocyclic 5-6-membered heterocyclic group,
containing one or two nitrogen atoms in the ring, which may have one or more amino groups as substituents;
X represents a C _2-6 alkenyl group which may have one or more substituents, a C _2-6 alkynyl group, a phenyl group which may have one or more substituents selected from an alkyl group or a halogen or phenyl C _1-6 alkyl group ;
Z ¹ and Z ² each independently represent a nitrogen atom or a group of the formula —CR ² =;
R ¹ and R ² each independently represent a group of the formula -A ⁰ -A ¹ -A ² (where A ⁰ is a single bond or a C _1-6 alkylene group, which may have 1-3 substituents selected from group B consisting of the following substituents; A ¹ represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O — CO—, a group represented by the formula —CO — O—, a group represented by the formula -NR ^A -, a group represented by the formula -CO-NR ^A -, a group representing hydrochloric formula -NR ^A -CO-, a group represented by the formula -SO ₂ -NR ^A -, or a group represented by the formula -NR ^A -SO ₂ -;
A ² and R ^A each independently represent a hydrogen atom, a halogen atom, a cyano group, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{6- 10} aryl group, 5-10 membered heteroaryl group, 4-8 membered heterocyclic group, 5-10 membered heteroaryl C _1-6 alkyl group, C _6-10 aryl C _1-6 alkyl group, or C _2-7 an alkylcarbonyl group;
moreover, A ² and R ^A , each independently, may have 1-3 substituents selected from the following group of substituents B:
when Z ² is a group of the formula —CR ² =, R ¹ and R ² may together form a 5-7 membered ring;
unless [1] R ¹ represents a hydrogen atom, Z ¹ represents a nitrogen atom and Z ² represents a —CH═ group; [2] Z ¹ represents a nitrogen atom and Z ² represents a group —C (OH) =;
<group of deputies B>
substituent group B is a group comprising a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C _1-6 alkyl group which may have one or more substituents, a C _3-8 cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _6-10 aryl group, 5-10 membered heteroaryl group, 4-8 membered heterocyclic group, C _1-6 alkoxy group, C _1-6 alkylthio group, the group represented by the formula —SO ₂ -NR ^B1 -R ^B2, a group represented by formula -NR ^B1 -CO-R ^B2, group, etc. dstavlennuyu formula -NR ^B1 -R ^B2 (where R ^B1 and R ^B2, each independently represent a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula -CO-R ^B3 (wherein R ^B3 represents 4-8 a membered heterocyclic group), a group represented by the formula —CO — R ^B4 —R ^B5 , and a group represented by the formula —CH ₂ —CO — R ^B4 —R ^B5 (where R ^B4 is a single bond, an oxygen atom, or a group represented by the formula -NR ^B6 -; R ^B5 and R ^B6 each independently represent a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, 5 10-membered heteroaryl group, 4-8-membered heterocycle C _1-6 alkyl group, C _6-10 aryl C _1-6 alkyl group or 5-10-membered heteroaryl C _1-6 alkyl group)). 2. The compound according to claim 1 or its salt or hydrate, where T ¹ represents a group of the following formula:

(where n = 0 and m = 0);
pyrrolidin-1-ilen group, which may contain an amino group;
piperidin-1-ilen group, which may contain an amino group. 3. The compound according to claim 1 or its salt or hydrate, where T ¹ represents a piperazin-1-ilen group or 3-aminopiperidin-1-ilen group. 4. The compound according to claim 1 or its salt or hydrate, where T ¹ represents a piperazin-1-ilen group. 5. The compound according to claim 1 or a salt or hydrate thereof, wherein X is a 3-methyl-2-buten-1-yl group, a 2-butyn-1-yl group, a benzyl group, or a 2-chlorophenyl group. 6. The compound according to claim 1 or its salt or hydrate, where X represents a 2-butyn-1-yl group. 7. The compound according to claim 1 or its salt or hydrate, where any of the groups Z ¹ or Z ² represents a nitrogen atom. 8. The compound according to claim 1 or its salt or hydrate, where Z ¹ represents a nitrogen atom; and Z ² is a group represented by the formula —CR ² =, where R ² is as defined in claim 1. 9. The compound according to claim 1 or its salt or hydrate, where Z ² represents a nitrogen atom; and Z ¹ is a group represented by the formula —CR ² =, where R ² is as defined in claim 1. 10. The compound according to claim 1 or its salt or hydrate,
where R ¹ represents a hydrogen atom or a group represented by the formula -A ¹⁰ -A ¹¹ -A ¹² (where A ¹⁰ represents a C _1-6 alkenyl group, which may have 1-3 substituents selected from the following substituent group C;
A ¹¹ represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group;
A ¹² represents a hydrogen atom, a C _6-10 aryl group which may have 1-3 substituents selected from the following substituent group C, a 5-10 membered heteroaryl group which may have 1-3 substituents selected from the following substituent groups C, a 5-10 membered heteroaryl C _1-6 alkyl group which may have 1-3 substituents selected from the following substituent group C, or a C _6-10 aryl C _1-6 alkyl group which may have 1 -3 substituents selected from the following substituent group C:
<substituent group C>
substituent group C is a group comprising a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR ^C1 —R ^C2 (where R ^C1 and R ^C2 each independently represent a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^C3 —R ^C4 , and a group represented by the formula —CH ₂ —CO — R ^{C3 C4} -R (where R ^C3 represents a single bond, an oxygen atom or a group represented by formula -NR ^C5 -; R ^C4 and R ^C5, azhdy independently represent a hydrogen atom or a C _1-6 alkyl group). 11. The compound according to claim 1 or its salt or hydrate, where R ¹ represents a hydrogen atom, a C _1-6 alkyl group which may have 1-3 substituents selected from the following substituent group C, 5-10 membered heteroaryl A C _1-6 alkyl group which may have 1-3 substituents selected from the following substituent group C, or a C _6-10 aryl C _1-6 alkyl group which may have 1-3 substituents selected from the following substituent group FROM:
<group of deputies C>
substituent group C represents a group including: a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR ^C1 —R ^C2 (where R ^C1 and R ^C2 each independently represent a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO — R ^C3 —R ^C4 , and a group represented by the formula —CH ₂ —CO — R ^C3 -R ^C4 (where R ^C3 represents a single bond, an oxygen atom or a group represented by the formula -NR ^C5 -; R ^C4 and R ^C5 each independently represent a hydrogen atom or a C _1-6 alkyl group). 12. The compound of claim 10 or a salt or hydrate thereof, wherein the substituent group C is a group comprising a cyano group, a C _1-6 alkoxy group, a C _2-7 alkoxycarbonyl group and a halogen atom. 13. The compound according to claim 1 or a salt or hydrate thereof, wherein R ¹ is a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenylethyl group, a 2-methoxyethyl group or a 4-methoxycarbonylpyridin-2-yl group. 14. The compound according to claim 1 or its salt or hydrate, where R ¹ represents a methyl group, or a 2-cyanobenzyl group. 15. The compound according to any one of claims 1 to 14 or its salt or hydrate, where R ² represents a hydrogen atom, a cyano group or a group represented by the formula -A ²¹ -A ²² ,
(where A ²¹ represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O — CO—, a group represented by the formula —CO — O—, a group represented by the formula —NR ^A2 -, a group represented by the formula —CO — NR ^A2 -, or a group represented by the formula —NR ^A2 —CO—;
A ²² and R ^A2 each independently represent a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group A 5-10 membered heteroaryl group, a 4-8 membered heterocyclic group, a 5-10 membered heteroaryl C _1-6 alkyl group, or a C _6-10 aryl C _1-6 alkyl group;
moreover, A ²² and R ^A2 , each independently, may have 1-3 substituents selected from the following substituents of group D:
<substituent group D>
substituent group D is a group comprising a hydroxyl group, a cyano group, a nitro group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR ^D1 —R ^D2 , (where R ^D1 and R ^D2 each independently represents a hydrogen atom or a C _1-6 alkyl group), a group represented by the formula —CO-R ^D3 (in which R ^D3 represents a 4-8 membered heterocyclic group) and a group represented by the formula -CO-R ^D4 -R ^D5 (where R ^D4 represents a single bond, an atom sour genus or group represented by Formula -NR ^D6 -; R ^D5 and R ^D6, each independently represent a hydrogen atom, a C _3-8 cycloalkyl group or a C _1-6 alkyl group)). 16. The compound according to any one of claims 1-14, or a salt or hydrate thereof, wherein R ² represents a hydrogen atom, a cyano group, a carboxy group, a C _2-7 alkoxycarbonyl group, a C _1-6 alkyl group, a group represented by the formula —CONR ^D7 R ^D8 (where R ^D7 and R ^D8 each independently represents a hydrogen atom or a C _1-6 alkyl group), or a group represented by the formula -A ²³ -A ²⁴ ,
(where A ²³ represents an oxygen atom, a sulfur atom or a group represented by the formula —NR ^A3 -;
A ²⁴ and R ^A3 each independently represent a hydrogen atom, a C _1-6 alkyl group which may have a substituent selected from the following substituent group D1, a C _3-8 cycloalkyl group which may have a substituent selected from the following substituent groups D1; a C _2-6 alkenyl group which may have a substituent selected from the following substituent group D1; a C _2-6 alkynyl group which may have a substituent selected from the following substituent group D1; a phenyl group which may have replace s selected from the group D1 shown below substituent or 5-10-membered heteroaryl group which may have a substituent selected from the group D1 shown below substituents:
<substituent group D1>
the group of substituents D1 is a group including
a carboxy group, a C _2-7 alkoxycarbonyl group, a C _1-6 alkyl group, a group represented by the formula —CONR ^D7 R ^D8 (where R ^D7 and R ^D8 each independently represent a hydrogen atom or a C _1-6 alkyl group), pyrrolidine -1-ylcarbonyl group, C _1-6 alkyl group and C _1-6 alkoxy group). 17. The compound according to any one of claims 1 to 14 or its salt or hydrate, where R ² represents a hydrogen atom, a cyano group, a C _1-6 alkoxy group or a group represented by the formula -A ²⁵ -A ²⁶ (where A ²⁵ represents an atom oxygen, a sulfur atom or a group represented by the formula —NR ^A4 -;
A ²⁶ and R ^A4 each independently represent a hydrogen atom, a C _1-6 alkyl group containing a substituent selected from the following substituent group D1, a C _3-8 cycloalkyl group having a substituent selected from the following substituent group D1, or a phenyl group having a substituent selected from the following D1 substituent group:
<substituent group D1>
the substituent group D1 includes a carboxy group, a C _2-7 alkoxycarbonyl group, a C _1-6 alkyl group, a group represented by the formula —CONR ^D7 R ^D8 (where R ^D7 and R ^D8 each independently represent a hydrogen atom or C _1-6 alkyl group), a pyrrolidin-1-ylcarbonyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group). 18. The compound according to any one of claims 1 to 14 or its salt or hydrate, where R ² represents a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group, or a group represented by the following formula:

(where A ²⁷ represents an oxygen atom, a sulfur atom, or —NH—;
A ²⁸ and A ²⁹ each independently represent a hydrogen atom or a C _1-6 alkyl group). 19. The compound according to any one of claims 1-14, or a salt or hydrate thereof, wherein R ² represents a hydrogen atom, a cyano group, or a 2-carbamoylphenyloxy group. 20. The compound according to claim 1 or its salt or hydrate, where the compound of formula (I) is
7- (2-butynyl) -2-cyano-1-methyl-8- (piperazin-1-yl) -1,7-dihydropurin-6-one. 21. The compound according to claim 1 or its salt or hydrate, where the compound of formula (I) is
3- (2-butynyl) -5-methyl-2- (piperazin-1-yl) -3,5-dihydroimidazo [4,5-d] pyridazin-4-one. 22. The compound according to claim 1 or its salt or hydrate, where the compound of formula (I) is
2- (3-aminopiperidin-1-yl) -3- (2-butynyl) -5-methyl-3,5-dihydroimidazo [4,5-d] pyridazin-4-one. 23. The compound according to claim 1 or its salt or hydrate, where the compound of formula (I) is
2- [7- (2-butynyl) -1-methyl-6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide. 24. The compound according to claim 1 or a salt or hydrate thereof, wherein the compound of formula (I) is
7- (2-butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purine-2-carbonitrile. 25. The compound according to claim 1 or a salt or hydrate thereof, wherein the compound of formula (I) is
2- [3- (2-butynyl) -4-oxo-2- (piperazin-1-yl) -3,4-dihydroimidazo [4,5-d] pyridazin-5-ylmethyl] benzonitrile. 26. The compound according to claim 1 or its salt or hydrate, where the compound of formula (I) is
2- [7- (2-butynyl) -1- (2-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide. 27. The compound according to claim 1 or a salt or hydrate thereof, wherein the compound of formula (I) is
2- [7- (2-butynyl) -1- (4-cyanobenzyl) -6-oxo-8- (piperazin-1-yl) -6,7-dihydro-1H-purin-2-yloxy] benzamide. 28. An inhibitor of dipeptidyl peptidase IV, containing the compound according to claim 1. 29. The pharmaceutical composition, which is an inhibitor of dipeptidyl peptidase IV, containing the compound according to claim 1 and an auxiliary agent used in the preparation of preparations. 30. A prophylactic or therapeutic agent containing a compound according to claim 1, for the treatment of diabetes mellitus, obesity, hyperlipidemia. 31. The prophylactic or therapeutic agent according to item 30 for the treatment of diabetes. 32. A method for the prevention or treatment of a disease in which the inhibition of dipeptidyl peptidase IV is effective, comprising administering to the patient a compound according to claim 1 or a salt or hydrate thereof in a pharmaceutically effective amount. 33. The use of a compound according to claim 1 or a salt or hydrate thereof for the preparation of a therapeutic or prophylactic agent for the treatment of a disease in which the inhibition of dipeptidyl peptidase IV is effective.